Glucopyranosyloxypyrazole derivatives and use thereof in medicines

ABSTRACT

The present invention provides glucopyranosyloxypyrazole derivatives represented by the general formula: 
     
       
         
         
             
             
         
       
     
     wherein R represents a hydrogen atom, a lower alkyl group or a group forming a prodrug; one of Q and T represents a group represented by the general formula: 
     
       
         
         
             
             
         
       
     
     (wherein P represents a hydrogen atom or a group forming a prodrug), while the other represents a lower alkyl group or a halo(lower alkyl) group; R 2  represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halo(lower alkyl) group or a halogen atom; and with the proviso that P does not represent a hydrogen atom when R represents a hydrogen atom or a lower alkyl group, or pharmaceutically acceptable salts thereof, which exert an inhibitory activity in human SGLT2 and have an improved oral absorption, and therefore are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, diabetic complications or obesity, and pharmaceutically acceptable salts thereof, and pharmaceutical uses thereof.

TECHNICAL FIELD

The present invention relates to glucopyranosyloxy-pyrazole derivativesor pharmaceutically acceptable salts thereof which are useful asmedicaments and pharmaceutical uses thereof.

More particularly, the present invention relates toglucopyranosyloxypyrazole derivatives represented by the generalformula:

wherein R represents a hydrogen atom, a lower alkyl group or a groupforming a prodrug; one of Q and T represents a

group represented by the general formula:(wherein P represents a hydrogen atom or a group forming a prodrug),while the other represents a lower alkyl group or a halo(lower alkyl)group; R² represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, a halo(lower alkyl) group or ahalogen atom; and with the proviso that P does not represent a hydrogenatom when R represents a hydrogen atom or a lower alkyl group, orpharmaceutically acceptable salts thereof, which are useful as agentsfor the prevention or treatment of a disease associated withhyperglycemia such as diabetes, diabetic complications or obesity, ofwhich glucopyranosyloxypyrazole derivatives, which have an inhibitoryactivity in human SGLT2, represented by the general formula:

wherein R⁰ represents a hydrogen atom or a lower alkyl group; one of Q⁰and T⁰ represents a group represented by

the general formula:while the other represents a lower alkyl group or a halo(lower alkyl)group; and R² represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, a halo(lower alkyl) group or ahalogen atom, are active forms, and to pharmaceutical uses thereof.

BACKGROUND ART

Diabetes is one of lifestyle-related diseases with the background ofchange of eating habit and lack of exercise. Hence, diet and exercisetherapies are performed in patients with diabetes. Furthermore, when itssufficient control and continuous performance are difficult, drugtreatment is simultaneously performed. Now, biguanides, sulfonylureasand insulin sensitivity enhancers have been employed as antidiabeticagents. However, biguanides and sulfonylureas show occasionally adverseeffects such as lactic acidosis and hypoglycemia, respectively. In acase of using insulin sensitivity enhancers, adverse effects such asedema occasionally are observed, and it is also concerned for advancingobesity. Therefore, in order to solve these problems, it has beendesired to develop antidiabetic agents having a new mechanism.

In recent years, development of new type antidiabetic agents has beenprogressing, which promote urinary glucose excretion and lower bloodglucose level by preventing excess glucose reabsorption at the kidney(J. Clin. Invest., Vol. 79, pp. 1510-1515 (1987)). In addition, it isreported that SGLT2 (Na⁺/glucose cotransporter 2) is present in the S1segment of the kidney's proximal tubule and participates mainly inreabsorption of glucose filtrated through glomerular (J. Clin. Invest.,Vol. 93, pp. 397-404 (1994)). Accordingly, inhibiting a human SGLT2activity prevents reabsorption of excess glucose at the kidney,subsequently promotes excreting excess glucose though the urine, andnormalizes blood glucose level. Therefore, fast development ofantidiabetic agents, which have a potent inhibitory activity in humanSGLT2 and have a new mechanism, has been desired. Also, since suchagents promote the excretion of excess glucose though the urine andconsequently the glucose accumulation in the body is decreased, they arealso expected to have a preventing or alleviating effect on obesity anda urinating effect. Furthermore, the agents are considered to be usefulfor various related diseases which occur accompanying the progress ofdiabetes or obesity due to hyperglycemia.

As compounds having pyrazole moiety, it is described that WAY-123783increased an amount of excreted glucose in normal mice. However, itseffects in human are not described at all (J. Med. Chem., Vol. 39, pp.3920-3928 (1996)).

DISCLOSURE OF THE INVENTION

The present inventors have studied earnestly to find compounds having aninhibitory activity in human SGLT2. As a result, it was found thatcompounds represented by the above general formula (I) are convertedinto glucopyranosyloxypyrazole derivatives represented by the abovegeneral formula (II) as their active forms in vivo, and show anexcellent inhibitory activity in human SGLT2 as mentioned below, therebyforming the basis of the present invention.

The present invention is to provide the followingglucopyranosyloxypyrazole derivatives or pharmaceutically acceptablesalts thereof, which exert an inhibitory activity in human SGLT2 in vivoand show an excellent hypoglycemic effect by excreting excess glucose inthe urine through preventing the reabsorption of glucose at the kidney,and to provide pharmaceutical uses thereof.

This is, the present invention relates to a glucopyranosyloxypyrazolederivative represented by the

general formula:

wherein R represents a hydrogen atom, a lower alkyl group or a groupforming a prodrug; one of Q and T represents a group represented by thegeneral formula:

(wherein P represents a hydrogen atom or a group forming a prodrug),while the other represents a lower alkyl group or a halo(lower alkyl)group; R² represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, a halo(lower alkyl) group or ahalogen atom; and with the proviso that P does not represent a hydrogenatom when R represents a hydrogen atom or a lower alkyl group, or apharmaceutically acceptable salt thereof.

Also, the present invention relates to a pharmaceutical composition, ahuman SGLT2 inhibitor and an agent for the prevention or treatment of adisease associated with hyperglycemia, which comprise as an activeingredient a glucopyranosyloxypyrazole derivative represented by theabove general formula (I) or a pharmaceutically acceptable salt thereof.

The present invention relates to a method for the prevention ortreatment of a disease associated with hyperglycemia, which comprisesadministering an effective amount of a glucopyranosyloxypyrazolederivative represented by the above general formula (I) or apharmaceutically acceptable salt thereof.

The present invention relates to a use of a glucopyranosyloxypyrazolederivative represented by the above general formula (I) or apharmaceutically acceptable salt thereof for the manufacture of apharmaceutical composition for the prevention or treatment of a diseaseassociated with hyperglycemia.

Furthermore, the present invention relates to a pharmaceuticalcombination which comprises (A) a glucopyranosyloxypyrazole derivativerepresented by the above general formula (I) or a pharmaceuticallyacceptable salt thereof, and (B) at least one member selected from thegroup consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer, aninsulin preparation, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme Areductase inhibitor, a fibric acid derivative, a β₃-adrenoceptoragonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, a cholesterol absorptioninhibitor, a lipase inhibitor, a microsomal triglyceride transferprotein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyl-transferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.

The present invention relates to a method for the prevention ortreatment of a disease associated with hyperglycemia, which comprisesadministering an effective amount of (A) a glucopyranosyloxypyrazolederivative represented by the above general formula (I) or apharmaceutically acceptable salt thereof, in combination with (B) atleast one member selected from the group consisting of an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, an insulin preparation, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation endproducts formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptorantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme Areductase inhibitor, a fibric acid derivative, a β₃-adrenoceptoragonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, a cholesterol absorptioninhibitor, a lipase inhibitor, a microsomal triglyceride transferprotein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyl-transferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.

The present invention relates to a use of (A) aglucopyranosyloxypyrazole derivative represented by the above generalformula (I) or a pharmaceutically acceptable salt thereof, and (B) atleast one member selected from the group consisting of an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, an insulin preparation, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation endproducts formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptorantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme Areductase inhibitor, a fibric acid derivative, a β₃-adrenoceptoragonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, a cholesterol absorptioninhibitor, a lipase inhibitor, a microsomal triglyceride transferprotein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyl-transferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer, for the manufacture of a pharmaceutical composition for theprevention or treatment of a disease associated with hyperglycemia.

In the present invention, the term “prodrug” means a compound which isconverted into a glucopyranosyloxypyrazole derivative represented by theabove general formula (II) as an active form thereof in vivo. Asexamples of groups forming prodrugs, in cases of such groups located ata hydroxy group, a hydroxy-protective group used generally as a prodrugsuch as a lower acyl group, a lower alkoxy-substituted (lower acyl)group, a lower alkoxycarbonyl-substituted (lower acyl) group, a loweralkoxycarbonyl group and a lower alkoxy-substituted (loweralkoxycarbonyl) group are illustrated, and in cases of such groupslocated at a nitrogen atom, an amino-protective group used generally asa prodrug such as a lower acyl group, a lower alkoxycarbonyl group, alower acyloxymethyl group and a lower alkoxycarbonyloxymethyl group areillustrated.

As the glucopyranosyloxypyrazole derivatives represented by the abovegeneral formula (I), for example,

compounds represented by the general formula:wherein R¹ represents a hydrogen atom, a lower alkyl group, a lower acylgroup, a lower alkoxycarbonyl group, a lower acyloxymethyl group or alower alkoxycarbonyloxymethyl group; one of Q¹ and T¹ represents a grouprepresented by

the general formula:(wherein P¹ represents a hydrogen atom, a lower acyl group, a loweralkoxy-substituted (lower acyl) group, a loweralkoxycarbonyl-substituted (lower acyl) group, a lower alkoxycarbonylgroup or a lower alkoxy-substituted (lower alkoxycarbonyl) group, whilethe other represents a lower alkyl group or a halo(lower alkyl) group;R² represents a hydrogen atom, a lower alkyl group, a lower alkoxygroup, a lower alkylthio group, a halo(lower alkyl) group or a halogenatom; and with the proviso that P¹ does not represent a hydrogen atomwhen R¹ represents a hydrogen atom or a lower alkyl group, areillustrated.

In the present invention, the term “lower alkyl group” means astraight-chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a tert-pentylgroup, a hexyl group or the like; the term “lower alkoxy group” means astraight-chained or branched alkoxy group having 1 to 6 carbon atomssuch as a methoxy group, an ethoxy group, a propoxy group, an isopropoxygroup, a butoxy group, an isobutoxy group, a sec-butoxy group, atert-butoxy group, a pentyloxy group, an isopentyloxy group, aneopentyloxy group, a tert-pentyloxy group, a hexyloxy group or thelike; and the term “lower alkylthio group” means a straight-chained orbranched alkylthio group having 1 to 6 carbon atoms such as a methylthiogroup, an ethylthio group, a propylthio group, an isopropylthio group, abutylthio group, an isobutylthio group, a sec-butylthio group, atert-butylthio group, a pentylthio group, an isopentylthio group, aneopentylthio group, a tert-pentylthio group, a hexylthio group or thelike. The term “halogen atom” means a fluorine atom, a chlorine atom, abromine atom or an iodine atom; and the term “halo(lower alkyl) group”means the above lower alkyl group substituted by different or same 1 to3 halogen atoms as defined above. The term “lower acyl group” means astraight-chained, branched or cyclic acyl group having 2 to 7 carbonatoms such as an acetyl group, a propionyl group, a butyryl group, anisobutyryl group, a pivaloyl group, a hexanoyl group and acyclohexylcarbonyl group; and the term “lower alkoxy-substituted (loweracyl) group means the above lower acyl group substituted by the abovelower alkoxy group. The term “lower alkoxycarbonyl group” means astraight-chained, branched or cyclic alkoxycarbonyl group having 2 to 7carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group,an isopropyloxycarbonyl group, an isobutyloxycarbonyl group and acyclohexyloxycarbonyl group; the term “lower alkoxycarbonyl-substituted(lower acyl) group means the above lower acyl group substituted by theabove lower alkoxycarbonyl group such as a 3-(ethoxycarbonyl)propionylgroup; and the term “lower alkoxy-substituted (lower alkoxycarbonyl)group means the above lower alkoxycarbonyl group substituted by theabove alkoxy group such as a 2-methoxyethoxycarbonyl group. Furthermore,the term “lower acyloxymethyl group” means a hydroxymethyl groupO-substituted by the above lower acyl group; and the term “loweralkoxycarbonyloxymethyl group” means a hydroxymethyl group O-substitutedby the above lower alkoxycarbonyl group.

In the substituent R, a hydrogen atom or a straight-chained or branchedalkyl group having 1 to 3 carbon atoms are preferable; a hydrogen atom,an ethyl group, a propyl group or an isopropyl group are morepreferable; and an isopropyl group is most preferable because ofmetabolic stability in human liver S9 fraction. In the substituent R², astraight-chained or branched alkyl group having 1 to 4 carbon atoms, astraight-chained or branched alkoxy group having 1 to 3 carbon atoms, ora straight-chained or branched alkylthio group having 1 to 3 carbonatoms are preferable; and an ethyl group, an ethoxy group, an isopropoxygroup, a methoxy group or a methylthio group are more preferable. In thesubstituents Q and T, it is preferable that the substituent Q is a loweralkyl group or a halo(lower alkyl) group. Among them, a lower alkylgroup is preferable; a straight-chained or branched alkyl group having 1to 3 carbon atoms is more preferable; and a methyl group is mostpreferable. In the substituent P, a lower acyl group and a loweralkoxycarbonyl group are preferable; a lower alkoxycarbonyl group ismore preferable; and a straight-chained or branched alkoxycarbonyl grouphaving 2 to 5 carbon atoms is most preferable. Concretely, amethoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonylgroup or an isobutoxycarbonyl group are preferable.

As the compounds of the present invention,4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-3-(6-O-methoxy-carbonyl-β-D-glucopyranosyloxy)-5-methylpyrazole,3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole,3-(6-O-isopropoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole,3-(6-O-isobutoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole,4-[(4-ethylphenyl)methyl]-1-isopropyl-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-5-methylpyrazole,3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-ethylphenyl)methyl]-1-isopropyl-5-methylpyrazole,4-[(4-ethylphenyl)methyl]-3-(6-O-isopropoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-5-methylpyrazole,4-[(4-ethylphenyl)methyl]-3-(6-O-isobutoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-5-methylpyrazole,4-[(4-ethoxyphenyl)methyl]-1-isopropyl-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-5-methylpyrazole,3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-ethoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole,4-[(4-ethoxyphenyl)methyl]-3-(6-O-isopropoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-5-methylpyrazole,4-[(4-ethoxyphenyl)methyl]-3-(6-O-isobutoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-5-methylpyrazole,1-isopropyl-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methylpyrazole,3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-4-[(4-methoxyphenyl)methyl]-5-methylpyrazole,3-(6-O-isopropoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-4-[(4-methoxyphenyl)methyl]-5-methylpyrazole,3-(6-O-isobutoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-4-[(4-methoxyphenyl)methyl]-5-methylpyrazole,1-isopropyl-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]pyrazole,3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-5-methyl-4-[(4-methylthiophenyl)methyl]pyrazole,3-(6-O-isopropoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-5-methyl-4-[(4-methylthiophenyl)methyl]pyrazole,3-(6-O-isobutoxycarbonyl-β-D-glucopyranosyloxy)-1-isopropyl-5-methyl-4-[(4-methylthiophenyl)methyl]pyrazoleand the like are preferable;4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-5-methylpyrazole,3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole,3-(6-O-isopropoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole,3-(6-O-isobutoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazoleand the like are more preferable; and

-   3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole    and the like are most preferable.

The compounds represented by the above general formula (I) of thepresent invention can be prepared by introducing hydroxy- and/oramino-protective groups capable of using generally as a prodrug into ahydroxy group and/or a nitrogen atom of a glucopyranosyloxypyrazolederivative represented by the above general formula (II) in usual way.

For example, the compounds of the present invention can be preparedusing a glucopyranosyloxypyrazole derivative represented by the abovegeneral formula (II) according to the following procedure or analogousprocedures thereof:

Wherein P⁰ represents a hydroxy-protective group such as a lower acylgroup, a lower alkoxy-substituted (lower acyl) group, a loweralkoxycarbonyl-substituted (lower acyl) group, a lower alkoxycarbonylgroup, a lower alkoxy-substituted (lower alkoxycarbonyl) group or abenzyloxycarbonyl group; P³ represents a lower acyl group or a loweralkoxycarbonyl group; P⁴ represents a lower acyl group; P⁵ represents alower alkoxycarbonyl group; R¹³ represents a lower acyl group or a loweralkoxycarbonyl group; R¹⁴ represents a lower acyloxymethyl group or alower alkoxycarbonyloxymethyl group; R¹⁵ represents an amino-protectivegroup such as a lower alkyl group, a lower acyl group, a loweralkoxy-substituted (lower acyl) group, a loweralkoxycarbonyl-substituted (lower acyl) group, a lower alkoxycarbonylgroup, a lower alkoxy-substituted (lower alkoxycarbonyl) group or abenzyloxycarbonyl group; one of Q⁶ and T⁶ represents a group representedby the general formula:

(wherein P⁰ has the same meaning as defined above), while the otherrepresents a lower alkyl group or a halo(lower alkyl) group; one of Q⁷and T⁷ represents a group

represented by the general formula:(wherein P³ has the same meaning as defined above), while the otherrepresents a lower alkyl group or a halo(lower alkyl) group; X¹ and X²represent a leaving group such as a bromine atom or a chlorine atom; andR⁰, R², Q⁰ and T⁰ have the same meanings as defined above.

Process 1

A prodrug represented by the above general formula (Ib) can be preparedby protecting the nitrogen atom of a glucopyranosyloxypyrazolederivative represented by the above general formula (II) with analiphatic acid anhydride represented by the above general formula (III)in an aliphatic acid such as acetic acid at usually 0° C. to refluxtemperature for usually 30 minutes to 1 day, or alternatively, byprotecting the nitrogen atom of a glucopyranosyloxypyrazole derivativerepresented by the above general formula (II) with a succinimidederivative represented by the above general formula (IV) in an inertsolvent such as tetrahydrofuran at usually room temperature to refluxtemperature for usually 1 hour to 1 day. The reaction time can beappropriately varied based on a used starting material, solvent andreaction temperature.

Process 2

A compound represented by the above general formula (V) can be preparedby introducing a hydroxymethyl group into the nitrogen atom of aglucopyranosyloxypyrazole derivative represented by the above generalformula (II) using formaldehyde in a various solvent. As the solventused in the reaction, water, methanol, ethanol, tetrahydrofuran,dichloromethane, ethyl acetate, N,N-dimethylformamide, acetonitrile, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process 3

A prodrug represented by the above general formula (Ic) can be preparedby protecting the hydroxymethyl group of a compound represented by theabove general formula (V) with a reagent for protecting represented bythe above general formula (VI) in the presence of a base such aspyridine, triethylamine, N,N-diisopropylethylamine, picoline, lutidine,collidine, quinuclidine, 1,2,2,6,6-pentamethylpiperidine or1,4-diazabicyclo[2.2.2]octane in an inert solvent or without anysolvent. As the inert solvent used in the reaction, dichloromethane,acetonitrile, ethyl acetate, diisopropyl ether, chloroform,tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetone,tert-butanol, a mixed solvent thereof and the like can be illustrated.The reaction temperature is usually from −40° C. to reflux temperature,and the reaction time is usually from 30 minutes to 2 days, varyingbased on a used starting material, solvent and reaction temperature.

Process 4

A prodrug represented by the above general formula (Id) or an analogouscompound thereof can be prepared by protecting the hydroxymethyl group,or the nitrogen atom and the hydroxymethyl group of aglucopyranosyloxypyrazole derivative represented by the above generalformula (II) with a reagent for protecting represented by the abovegeneral formula (VII) in the presence of a base such as pyridine,triethylamine, N,N-diisopropylethylamine, picoline, lutidine, collidine,quinuclidine, 1,2,2,6,6-pentamethylpiperidine or1,4-diazabicyclo[2.2.2]octane in an inert solvent or without anysolvent. As the inert solvent used in the reaction, dichloromethane,acetonitrile, ethyl acetate, diisopropyl ether, chloroform,tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetone,tert-butanol, a mixed solvent thereof and the like can be illustrated.The reaction temperature is usually from −40° C. to reflux temperature,and the reaction time is usually from 30 minutes to 2 days, varyingbased on a used starting material, solvent and reaction temperature.

Process 5

A prodrug represented by the above general formula (Ie) or an analogouscompound thereof can be prepared by subjecting a compound represented bythe above general formula (Id) to deacylation in the presence of a weakbase such as sodium hydrogen carbonate, sodium carbonate or potassiumcarbonate in an alcoholic solvent such as methanol or ethanol. Thereaction temperature is usually from 0° C. to reflux temperature, andthe reaction time is usually from 15 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Process 6

A prodrug represented by the above general formula (If) or an analogouscompound thereof can be prepared by protecting the nitrogen atom of acompound represented by the above general formula (Ie) with an aliphaticacid anhydride represented by the above general formula (III) in analiphatic acid such as acetic acid at usually 0° C. to refluxtemperature for usually 30 minutes to 1 day, alternatively, with asuccinimide derivative represented by the above general formula (IV) inan inert solvent such as tetrahydrofuran at usually room temperature toreflux temperature for 1 hour to 1 day, and further alternatively, witha reagent for protecting represented by the above general formula (VI)in the presence of a base such as pyridine, triethylamine,N,N-diisopropylethylamine, picoline, lutidine, collidine, quinuclidine,1,2,2,6,6-pentamethylpiperidine or 1,4-diazabicyclo[2.2.2]octane in aninert solvent such as dichloromethane, acetonitrile, ethyl acetate,diisopropyl ether, chloroform, tetrahydrofuran, 1,2-dimethoxyethane,1,4-dioxane, acetone, tert-butanol or a mixed solvent thereof, orwithout any solvent at usually −40° C. to reflux temperature for 30minutes to 2 days. The reaction time can be appropriately varied basedon a used starting material, solvent and reaction temperature.

Process 7

A compound represented by the above general formula (VIII) can beprepared by introducing a hydroxymethyl group into the nitrogen atom ofa compound represented by the above general formula (Ie) usingformaldehyde in a various solvent. As the solvent used in the reaction,water, methanol, ethanol, tetrahydrofuran, dichloromethane, ethylacetate, N,N-dimethylformamide, acetonitrile, a mixed solvent thereofand the like can be illustrated. The reaction temperature is usuallyfrom 0° C. to reflux temperature, and the reaction time is usually from30 minutes to 1 day, varying based on a used starting material, solventand reaction temperature.

Process 8

A prodrug represented by the above general formula (Ig) or an analogouscompound thereof can be prepared by protecting the hydroxymethyl groupof a compound represented by the above general formula (VIII) with areagent for protecting represented by the above general formula (VI) inthe presence of a base such as pyridine, triethylamine,N,N-diisopropylethylamine, picoline, lutidine, collidine, quinuclidine,1,2,2,6,6-penta-methylpiperidine or 1,4-diazabicyclo[2.2.2]octane in aninert solvent or without any solvent. As the inert solvent used in thereaction, dichloromethane, acetonitrile, ethyl acetate, diisopropylether, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,acetone, tert-butanol, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from −40° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 2 days,varying based on a used starting material, solvent and reactiontemperature.

Process 9

A prodrug represented by the above general formula (Ih) can be preparedby subjecting a compound represented by the above general formula (Ig)to deprotection by catalytic hydrogenation in the presence of apalladium catalyst such as palladium carbon in an inert solvent. As theinert solvent used in the reaction, methanol, ethanol, tetrahydrofuran,ethyl acetate, a mixed solvent thereof and the like can be illustrated.The reaction temperature is usually from 0° C. to reflux temperature,and the reaction time is usually from 30 minutes to 1 day, varying basedon a used starting material, solvent and reaction temperature.

For example, the compounds represented by the above general formula (II)which are used as starting materials in the aforementioned productionprocess can be prepared according to the following procedure:

wherein X³ and Y represent a leaving group such as a halogen atom, amesyloxy group or a tosyloxy group; R³ represents a lower alkyl group ora halo(lower alkyl) group; R⁴ represents a methyl group or an ethylgroup; R⁵ represents a lower alkyl group; one of Q⁸ and T⁸ represents a2,3,4,6-tatra-O-acetyl-β-D-glucopyranosyloxy group, while the otherrepresents a lower alkyl group or a halo(lower alkyl) group; and R⁰, R²,Q⁰ and T⁰ have the same meanings as defined above.

Process A

A compound represented by the above general formula (XI) can be preparedby condensing a benzyl derivative represented by the above generalformula (IX) with a ketoacetate represented by the above general formula(X) in the presence of a base such as sodium hydride or potassiumtert-butoxide in an inert solvent. As the inert solvent used in thereaction, 1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 1 hour to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process B

A pyrazolone derivative represented by the above general formula (XII)can be prepared by condensing a compound represented by the abovegeneral formula (XI) with hydrazine or hydrazine monohydrate in an inertsolvent. As the inert solvent used in the reaction, toluene,tetrahydrofuran, chloroform, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 1 hour to 1day, varying based on a used starting material, solvent and reactiontemperature. The obtained pyrazolone derivative represented by the abovegeneral formula (XII) can be also used in process C after convertinginto a salt thereof in usual way.

Process C

In case of pyrazolone derivatives represented by the above generalformula (XII) wherein R³ is a lower alkyl group, a correspondingcompound represented by the above general formula (XIV) can be preparedby subjecting a corresponding pyrazolone derivative represented by theabove general formula (XII) to glycosidation usingacetobromo-α-D-glucose in the presence of a base such as silvercarbonate in an inert solvent, and subjecting the resulting compound toN-alkylation using an alkylating agent represented by the above generalformula (XIII) in the presence of a base such as potassium carbonate inan inert solvent as occasion demands. As the solvent used in theglycosidation reaction, tetrohydrofuran and the like can be illustrated.The reaction temperature is usually from room temperature to refluxtemperature, and the reaction time is usually from 1 hour to 1 day,varying based on a used starting material, solvent and reactiontemperature. As the solvent used in the N-alkylation reaction,acetonitrile, N,N-dimethylformamide, tetrohydro-furan, a mixed solventthereof and the like can be illustrated. The reaction temperature isusually from room temperature to reflux temperature, and the reactiontime is usually from 1 hour to 1 day, varying based on a used startingmaterial, solvent and reaction temperature.

In case of pyrazolone derivatives represented by the above generalformula (XII) wherein R³ is a halo(lower alkyl) group, a correspondingcompound represented by the above general formula (XIV) can be preparedby subjecting a corresponding pyrazolone derivative represented by theabove general formula (XII) to glycosidation usingacetobromo-α-D-glucose in the presence of a base such as potassiumcarbonate in an inert solvent, and subjecting the resulting compound toN-alkylation using an alkylating agent represented by the above generalformula (XIII) in the presence of a base such as potassium carbonate inan inert solvent as occasion demands. As the solvent used in theglycosidation reaction, acetonitrile, tetrohydrofuran and the like canbe illustrated. The reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from1 hour to 1 day, varying based on a used starting material, solvent andreaction temperature. As the solvent used in the N-alkylation reaction,acetonitrile, N,N-dimethylformamide, tetrohydrofuran, a mixed solventthereof and the like can be illustrated. The reaction temperature isusually from room temperature to reflux temperature, and the reactiontime is usually from 1 hour to 1 day, varying based on a used startingmaterial, solvent and reaction temperature.

In the compound represented by the above general formula (XII) asstarting materials, there are the following three tautomers, varyingbased on the change of reaction conditions:

wherein R² and R³ have the same meanings as defined above.

The obtained compounds represented by the above general formula (XIV)can be also used in process D after converting into a salt thereof inusual way.

Process D

A glucopyranosyloxypyrazole represented by the above general formula(II) can be prepared by subjecting a compound represented by the abovegeneral formula (XIV) to hydrolysis. As the solvent used in thereaction, methanol, ethanol, tetrahydrofuran, water, a mixed solventthereof and the like can be illustrated, and as the base used, sodiumhydroxide, sodium ethoxide and the like can be illustrated. The reactiontemperature is usually from 0° C. to room temperature, and the reactiontime is usually from 30 minutes to 6 hours, varying based on a usedstarting material, solvent and reaction temperature.

Of the compounds represented by the above general formula (II) which arealso used as starting materials in the aforementioned productionprocess, compounds wherein the substituent R⁰ is a lower alkyl group canbe also prepared according to the following procedure:

wherein R², R⁵, Q⁰, T⁰ and X³ have the same meanings as defined above.

Process E

A compound represented by the above general formula (IIb) can beprepared by subjecting a compound represented by the above generalformula (IIa) to N-alkylation using an N-alkylating agent represented bythe above general formula (XIII) in the presence of a base such aspotassium carbonate or cesium carbonate, and occasionally a catalyticamount of sodium iodide in an inert solvent. As the inert solvent usedin the reaction, N,N-dimethylformamide, 1,2-dimethoxyethane, dimethylsulfoxide, tetrahydrofuran, ethanol, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from10 minutes to 1 day, varying based on a used starting material, solventand reaction temperature.

The compounds represented by the above general formula (I) of thepresent invention obtained by the above production processes can beisolated and purified by conventional separation means such asfractional recrystallization, purification using chromatography, solventextraction and solid phase extraction.

The glucopyranosyloxypyrazole derivatives represented by the abovegeneral formula (I) of the present invention can be converted into theirpharmaceutically acceptable salts in the usual way. Examples of suchsalts include acid addition salts with mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid and the like, acid addition salts withorganic acids such as formic acid, acetic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citricacid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalicacid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid,glutamic acid, aspartic acid, adipic acid, oleic acid, stearic acid andthe like, and salts with inorganic bases such as a sodium salt, apotassium salt, a calcium salt, a magnesium salt and the like.

The prodrugs represented by the above general formula (I) of the presentinvention include their solvates with pharmaceutically acceptablesolvents such as ethanol and water.

Of the compounds represented by the above general formula (I) of thepresent invention, there are two optical isomers, R-isomer and S-isomer,in each compound having an asymmetric carbon atom excluding theglucopyranosyloxy moiety. In the present invention, either of R-isomeror S-isomer can be employed, and a mixture of both isomers can be alsoemployed.

The prodrugs represented by the above general formula (I) of the presentinvention are converted into glucopyranosyloxypyrazole derivativesrepresented by the above general formula (II) as their active forms invivo, and show an excellent inhibitory activity in human SGLT2. On theother hand, since WAY-123783 has an extremely weak inhibitory activityin human SGLT2, it can not be expected that it exerts an enough effectas a human SGLT2 inhibitor. In addition, the prodrugs represented by theabove general formula (I) of the present invention have an improved oralabsorption, and pharmaceutical compositions comprising as an activeingredient the prodrug have a highly usefulness as oral formulations.Therefore, the prodrugs of the present invention are extremely useful asagents for the prevention or treatment of a disease associated withhyperglycemia such as diabetes, diabetic complications (e.g.,retinopathy, neuropathy, nephropathy, ulcer, macroangiopathy), obesity,hyperinsulinemia, glucose metabolism disorder, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder,atherosclerosis, hypertension, congestive heart failure, edema,hyperuricemia, gout or the like.

Furthermore, the compounds of the present invention can be suitably usedin combination with at least one member selected from drugs other thanSGLT2 inhibitors. Examples of the drugs which can be used in combinationwith the compounds of the present invention include an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, an insulin preparation, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation endproducts formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptorantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor (PDGF), a platelet-derivedgrowth factor (PDGF) analogue (e.g., PDGF-AA, PDGF-BB, PDGF-AB),epidermal growth factor (EGF), nerve growth factor, a carnitinederivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol,sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme A reductaseinhibitor, a fibric acid derivative, a β₃-adrenoceptor agonist, anacyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, athyroid hormone receptor agonist, a cholesterol absorption inhibitor, alipase inhibitor, a microsomal triglyceride transfer protein inhibitor,a lipoxygenase inhibitor, a carnitine palmitoyltransferase inhibitor, asqualene synthase inhibitor, a low-density lipoprotein receptorenhancer, a nicotinic acid derivative, a bile acid sequestrant, asodium/bile acid cotransporter inhibitor, a cholesterol ester transferprotein inhibitor, an appetite suppressant, an angiotensin-convertingenzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin IIreceptor antagonist, an endothelin-converting enzyme inhibitor, anendothelin receptor antagonist, a diuretic agent, a calcium antagonist,a vasodilating antihypertensive agent, a sympathetic blocking agent, acentrally acting antihypertensive agent, an α₂-adrenoceptor agonist, anantiplatelets agent, a uric acid synthesis inhibitor, a uricosuric agentand a urinary alkalinizer.

In case of uses of the compound of the present invention in combinationwith the above one or more drugs, the present invention includes eitherdosage forms of simultaneous administration as a single preparation orseparated praparations in way of same or different administration route,and administration at different dosage intervals as separatedpreparations in way of same or different administration route. Apharmaceutical combination comprising the compound of the presentinvention and the above one or more drugs includes both dosage forms asa single preparation and separated preparations for combination asmentioned above.

The compounds of the present invention can obtain more advantageouseffects than additive effects in the prevention or treatment of theabove diseases when using suitably in combination with the above drugs.Also, the administration dose can be decreased in comparison withadministration of either drug alone, or adverse effects ofcoadministrated drugs other than SGLT2 inhibitors can be avoided ordeclined.

Concrete compounds as the above drugs used for combination andpreferable diseases to be treated are exemplified as follows. However,the present invention is not limited thereto, and for example, theconcrete compounds include their free compounds, and their or otherpharmaceutically acceptable salts.

As insulin sensitivity enhancers, peroxisome proliferator-activatedreceptor-γ agonists such as troglitazone, pioglitazone hydrochloride,rosiglitazone maleate, sodium darglitazone, GI-262570, isaglitazone,LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929,ciglitazone, sodium englitazone and NIP-221, peroxisomeproliferator-activated receptor-α agonists such as GW-9578 andBM-170744, peroxisome proliferator-activated receptor-α/γ agonists suchas GW-409544, KRP-297, N,N-622, CLX-0940, LR-90, SB-219994, DRF-4158 andDRF-MDX8, retinoid X receptor agonists such as ALRT-268, AGN-4204,MX-6054, AGN-194204, LG-100754 and bexarotene, and other insulinsensitivity enhancers such as reglixane, ONO-5816, MBX-102, CRE-1625,FK-614, CLX-0901, CRE-1633, N,N-2344, BM-13125, BM-501050, HQL-975,CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929,AR-H049020 and GW-501516 are illustrated. Insulin sensitivity enhancersare used preferably for diabetes, diabetic complications, obesity,hyperinsulinemia, glucose metabolism disorder, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder oratherosclerosis, and more preferably for diabetes, hyper-insulinemia orglucose metabolism disorder because of improving the disturbance ofinsulin signal transduction in peripheral tissues and enhancing glucoseuptake into the tissues from the blood, leading to lowering of bloodglucose level.

As glucose absorption inhibitors, α-glucosidase inhibitors such asacarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25,637,camiglibose and MDL-73,945, and α-amylase inhibitors such as AZM-127 areillustrated. Glucose absorption inhibitors are used preferably fordiabetes, diabetic complications, obesity, hyperinsulinemia or glucosemetabolism disorder, and more preferably for diabetes or glucosemetabolism disorder because of inhibiting the gastrointestinal enzymaticdigestion of carbohydrates contained in foods, and inhibiting ordelaying the absorption of glucose into the body.

As biguanides, phenformin, buformin hydrochloride, metforminhydrochloride or the like are illustrated. Biguanides are usedpreferably for diabetes, diabetic complications, hyperinsulinemia orglucose metabolism disorder, and more preferably for diabetes,hyperinsulinemia or glucose metabolism disorder because of loweringblood glucose level by inhibitory effects on hepatic gluconeogenesis,accelerating effects on anaerobic glycolysis in tissues or improvingeffects on insulin resistance in peripheral tissues.

As insulin secretion enhancers, tolbutamide, chlorpropamide, tolazamide,acetohexamide, glyclopyramide, glyburide (glibenclamide), gliclazide,1-butyl-3-metanilyl-urea, carbutamide, glibornuride, glipizide,gliquidone, glisoxapide, glybuthiazol, glybuzole, glyhexamide, sodiumglymidine, glypinamide, phenbutamide, tolcyclamide, glimepiride,nateglinide, mitiglinide calcium hydrate, repaglinide or the like areillustrated. Insulin secretion enhancers are used preferably fordiabetes, diabetic complications or glucose metabolism disorder, andmore preferably for diabetes or glucose metabolism disorder because oflowering blood glucose level by acting on pancreatic 0-cells andenhancing the insulin secretion.

As insulin preparations, human insulin, human insulin analogues,animal-deprived insulin or the like are illustrated. Insulinpreparations are used preferably for diabetes, diabetic complications orglucose metabolism disorder, and more preferably for diabetes or glucosemetabolism disorder.

As glucagon receptor antagonists, BAY-27-9955, NNC-92-1687 or the likeare illustrated; as insulin receptor kinase stimulants, TER-17411,L-783281, KRX-613 or the like are illustrated; as tripeptidyl peptidaseII inhibitors, UCL-1397 or the like are illustrated; as dipeptidylpeptidase IV inhibitors, NVP-DPP728A, TSL-225, P-32/98 or the like areillustrated; as protein tyrosine phosphatase 1B inhibitors, PTP-112,OC-86839, PNU-177496 or the like are illustrated; as glycogenphosphorylase inhibitors, N,N-4201, CP-368296 or the like areillustrated; as fructose-bisphosphatase inhibitors, R-132917 or the likeare illustrated; as pyruvate dehydrogenase inhibitors, AZD-7545 or thelike are illustrated; as hepatic gluconeogenesis inhibitors, FR-225659or the like are illustrated; as glucagon-like peptide-1 analogues,exendin-4, CJC-1131 or the like are illustrated; as glucagon-likepeptide 1 agonists; AZM-134, LY-315902 or the like are illustrated; andas amylin, amylin analogues or amylin agonists, pramlintide acetate orthe like are illustrated. These drugs, glucose-6-phosphatase inhibitors,D-chiroinsitol, glycogen synthase kinase-3 inhibitors, glucagon-likepeptide-1 are used preferably for diabetes, diabetic complications,hyperinsulinemia or glucose metabolism disorder, and more preferably fordiabetes or glucose metabolism disorder.

As aldose reductase inhibitors, ascorbyl gamolenate, tolrestat,epairestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598,fidarestat, sorbinil, ponalrestat, risarestat, zenarestat, minalrestat,methosorbinil, AL-1567, imirestat, M-16209, TAT, AD-5467, zopolrestat,AS-3201, NZ-314, SG-210, JTT-811, lindolrestat or the like areillustrated. Aldose reductase inhibitors are preferably used fordiabetic complications because of inhibiting aldose reductase andlowering excessive intracellular accumulation of sorbitol in acceleratedpolyol pathway which are in continuous hyperglycemic condition in thetissues in diabetic complications.

As advanced glycation endproducts formation inhibitors, pyridoxamine,OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride or the like areillustrated. Advanced glycation endproducts formation inhibitors arepreferably used for diabetic complications because of inhibitingformation of advanced glycation endproducts which are accelerated incontinuous hyperglycemic condition in diabetes and declining of cellulardamage.

As protein kinase C inhibitors, LY-333531, midostaurin or the like areillustrated. Protein kinase C inhibitors are preferably used fordiabetic complications because of inhibiting of protein kinase Cactivity which is accelerated in continuous hyperglycemic condition indiabetes.

As γ-aminobutyric acid receptor antagonists, topiramate or the like areillustrated; as sodium channel antagonists, mexiletine hydrochloride,oxcarbazepine or the like are illustrated; as transcrit factor NF-κBinhibitors, dexlipotam or the like are illustrated; as lipid peroxidaseinhibitors, tirilazad mesylate or the like are illustrated; asN-acetylated-α-linked-acid-dipeptidase inhibitors, GPI-5693 or the likeare illustrated; and as carnitine derivatives, carnitine, levacecaminehydrochloride, levocarnitine chloride, levocarnitine, ST-261 or the likeare illustrated. These drugs, insulin-like growth factor-I,platelet-derived growth factor, platelet derived growth factoranalogues, epidermal growth factor, nerve growth factor, uridine,5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide and Y-128are preferably used for diabetic complications.

As hydroxymethylglutaryl coenzyme A reductase inhibitors, sodiumcerivastatin, sodium pravastatin, lovastatin, simvastatin, sodiumfluvastatin, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101,BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987,calcium pitavastatin, calcium rosuvastatin, colestolone, dalvastatin,acitemate, mevastatin, crilvastatin, BMS-180431, BMY-21950,glenvastatin, carvastatin, BMY-22089, bervastatin or the like areillustrated. Hydroxymethylglutaryl coenzyme A reductase inhibitors areused preferably for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, andmore preferably for hyperlipidemia, hypercholesterolemia oratherosclerosis because of lowering blood cholesterol level byinhibiting hydroxymethylglutaryl coenzyme A reductase.

As fibric acid derivatives, bezafibrate, beclobrate, binifibrate,ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate, clofibricacid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate,ronifibrate, simfibrate, theofibrate, AHL-157 or the like areillustrated. Fibric acid derivatives are used preferably forhyper-insulinemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, andmore preferably for hyperlipidemia, hypertriglyceridemia oratherosclerosis because of activating hepatic lipoprotein lipase andenhancing fatty acid oxidation, leading to lowering of bloodtriglyceride level.

As β₃-adrenoceptor agonists, BRL-28410, SR-58611A, ICI-198157, ZD-2079,BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413,SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552,D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353,N-5984, GW-2696 or the like are illustrated. β₃-Adrenoceptor agonistsare used preferably for obesity, hyperinsulinemia, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia or lipid metabolism disorder,and more preferably for obesity or hyperinsulinemia because ofstimulating 3-adrenoceptor in adipose tissue and enhancing the fattyacid oxidation, leading to induction of energy expenditure.

As acyl-coenzyme A cholesterol acyltransferase inhibitors, NTE-122,MCC-147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676, P-06139,CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115,FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-C8-434, avasimibe,CI-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546, YM-17E,lecimibide, 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe or thelike are illustrated. Acyl-coenzyme A cholesterol acyltransferaseinhibitors are used preferably for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia or lipid metabolism disorder, and more preferablyfor hyperlipidemia or hypercholesterolemia because of lowering bloodcholesterol level by inhibiting acyl-coenzyme A cholesterolacyltransferase.

As thyroid hormone receptor agonists, sodium liothyronine, sodiumlevothyroxine, KB-2611 or the like are illustrated; as cholesterolabsorption inhibitors, ezetimibe, SCH-48461 or the like are illustrated;as lipase inhibitors, orlistat, ATL-962, AZM-131, RED-103004 or the likeare illustrated; as carnitine palmitoyltransferase inhibitors, etomoxiror the like are illustrated; as squalene synthase inhibitors,SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393,ER-27856 or the like are illustrated; as nicotinic acid derivatives,nicotinic acid, nicotinamide, nicomol, niceritrol, acipimox, nicorandilor the like are illustrated; as bile acid sequestrants, colestyramine,colestilan, colesevelam hydrochloride, GT-102-279 or the like areillustrated; as sodium/bile acid cotransporter inhibitors, 264W94,S-8921, SD-5613 or the like are illustrated; and as cholesterol estertransfer protein inhibitors, PNU-107368E, SC-795, JTT-705, CP-529414 orthe like are illustrated. These drugs, probcol, microsomal trigylceridetransfer protein inhibitors, lipoxygenase inhibitors and low-densitylipoprotein receptor enhancers are preferably used for hyperlipidemia,hypercholesterolemia, hypertriglyceridemia or lipid metabolism disorder.

As appetite suppressants, monoamine reuptake inhibitors, serotoninreuptake inhibitors, serotonin releasing stimulants, serotonin agonists(especially 5HT_(2C)-agonists), noradrenaline reuptake inhibitors,noradrenaline releasing stimulants, α₁-adrenoceptor agonists,β₂-adrenoceptor agonists, dopamine agonists, cannabinoid receptorantagonists, γ-aminobutyric acid receptor antagonists, H₃-histamineantagonists, L-histidine, leptin, leptin analogues, leptin receptoragonists, melanocortin receptor agonists (especially, MC3-R agonists,MC4-R agonists), α-melanocyte stimulating hormone, cocaine- andamphetamine-regulated transcript, mahogany protein, enterostatinagonists, calcitonin, calcitonin-gene-related peptide, bombesin,cholecystokinin agonists (especially CCK-A agonists),corticotropin-releasing hormone, corticotrophin-releasing hormoneanalogues, corticotropin-releasing hormone agonists, urocortin,somatostatin, somatostatin analogues, somatostatin receptor agonists,pituitary adenylate cyclase-activating peptide, brain-derivedneurotrophic factor, ciliary neurotrophic factor, thyrotropin-releasinghormone, neurotensin, sauvagine, neuropeptide Y antagonists, opioidpeptide antagonists, galanin antagonists, melanin-concentrating hormoneantagonists, agouti-related protein inhibitors and orexin receptorantagonists are illustrated. Concretely, as monoamine reuptakeinhibitors, mazindol or the like are illustrated; as serotonin reuptakeinhibitors, dexfenfluramine hydrochloride, fenfluramine, sibutraminehydrochloride, fluvoxamine maleate, sertraline hydrochloride or the likeare illustrated; as serotonin agonists, inotriptan, (+)-norfenfluramineor the like are illustrated; as noradrenaline reuptake inhibitors,bupropion, GW-320659 or the like are illustrated; as noradrenalinereleasing stimulants, rolipram, YM-992 or the like are illustrated; asβ₂-adrenoceptor agonists, amphetamine, dextroamphetamine, phentermine,benzphetamine, methamphetamine, phendimetrazine, phenmetrazine,diethylpropion, phenylpropanolamine, clobenzorex or the like areillustrated; as dopamine agonists, ER-230, doprexin, bromocriptinemesylate or the like are illustrated; as cannabinoid receptorantagonists, rimonabant or the like are illustrated; as γ-aminobutyricacid receptor antagonists, topiramate or the like are illustrated; asH₃-histamine antagonists, GT-2394 or the like are illustrated; asleptin, leptin analogues or leptin receptor agonists, LY-355101 or thelike are illustrated; as cholecystokinin agonists (especially CCK-Aagonists), SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849,GI-248573, GW-7178, GI-181771, GW-7854, A-71378 or the like areillustrated; and as neuropeptide Y antagonists, SR-120819-A, PD-160170,NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01,J-115814 or the like are illustrated. Appetite suppressants are usedpreferably for diabetes, diabetic complications, obesity, glucosemetabolism disorder, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder, atherosclerosis,hypertension, congestive heart failure, edema, hyperuricemia or gout,and more preferably for obesity because of stimulating or inhibiting theactivities of intracerebral monoamines or bioactive peptides in centralappetite regulatory system and suppressing the appetite, leading toreduction of energy intake.

As angiotensin-converting enzyme inhibitors, captopril, enalaprimaleate, alacepril, delapril hydrochloride, ramipril, lisinopril,imidapril hydrochloride, benazepril hydrochloride, ceronaprilmonohydrate, cilazapril, sodium fosinopril, perindopril erbumine,calcium moveltipril, quinapril hydrochloride, spirapril hydrochloride,temocapril hydrochloride, trandolapril, calcium zofenopril, moexiprilhydrochloride, rentiapril or the like are illustrated.Angiotensin-converting enzyme inhibitors are preferably used fordiabetic complications or hypertension.

As neutral endopeptidase inhibitors, omapatrilat, MDL-100240,fasidotril, sampatrilat, GW-660511×, mixanpril, SA-7060, E-4030,SLV-306, ecadotril or the like are illustrated. Neutral endopeptidaseinhibitors are preferably used for diabetic complications orhypertension.

As angiotensin II receptor antagonists, candesartan cilexetil,candesartan cilexetil/hydrochlorothiazide, potassium losartan,eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174,L-158809, EXP-3312, olmesartan, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701 or the like are illustrated. Angiotensin II receptorantagonists are preferably used for diabetic complications orhypertension.

As endothelin-converting enzyme inhibitors, CGS-31447, CGS-35066,SM-19712 or the like are illustrated; as endothelin receptorantagonists, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355,PD-180988, sodium sitaxsentan, BMS-193884, darusentan, TBC-3711,bosentan, sodium tezosentan, J-104132, YM-598, S-0139, SB-234551,RPR-118031A, ATZ-1993, R^(O)-61-1790, ABT-546, enlasentan, BMS-207940 orthe like are illustrated. These drugs are preferably used for diabeticcomplications or hypertension, and more preferably for hypertension.

As diuretic agents, chlorthalidone, metolazone, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, methyclothiazide, indapamide,tripamide, mefruside, azosemide, etacrynic acid, torasemide, piretanide,furosemide, bumetanide, meticrane, potassium canrenoate, spironolactone,triamterene, aminophylline, cicletanine hydrochloride, LLU-α,PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin,acetazolamide, methazolamide, FR-179544, OPC-31260, lixivaptan,conivaptan hydrochloride or the like are illustrated. Diuretic drugs arepreferably used for diabetic complications, hypertension, congestiveheart failure or edema, and more preferably for hypertension, congestiveheart failure or edema because of reducing blood pressure or improvingedema by increasing urinary excretion.

As calcium antagonists, aranidipine, efonidipine hydrochloride,nicardipine hydrochloride, barnidipine hydrochloride, benidipinehydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine,nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besilate,pranidipine, lercanidipine hydrochloride, isradipine, elgodipine,azelnidipine, lacidipine, vatanidipine hydrochloride, lemildipine,diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride,S-verapamil, fasudil hydrochloride, bepridil hydrochloride, gallopamilhydrochloride or the like are illustrated; as vasodilatingantihypertensive agents, indapamide, todralazine hydrochloride,hydralazine hydrochloride, cadralazine, budralazine or the like areillustrated; as sympathetic blocking agents, amosulalol hydrochloride,terazosin hydrochloride, bunazosin hydrochloride, prazosinhydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol,metoprolol tartrate, carvedilol, nipradilol, celiprolol hydrochloride,nebivolol, betaxolol hydrochloride, pindolol, tertatolol hydrochloride,bevantolol hydrochloride, timolol maleate, carteolol hydrochloride,bisoprolol hemifumarate, bopindolol malonate, nipradilol, penbutololsulfate, acebutolol hydrochloride, tilisolol hydrochloride, nadolol,urapidil, indoramin or the like are illustrated; as centrally actingantihypertensive agents, reserpine or the like are illustrated; and asα₂-adrenoceptor agonists, clonidine hydrochloride, methyldopa, CHF-1035,guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine,talipexole hydrochloride or the like are illustrated. These drugs arepreferably used for hypertension.

As antiplatelets agents, ticlopidine hydrochloride, dipyridamole,cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dilazepdihydrochloride, trapidil, beraprost sodium, aspirin or the like areillustrated. Antiplatelets agents are preferably used foratherosclerosis or congestive heart failure.

As uric acid synthesis inhibitors, allopurinol, oxypurinol or the likeare illustrated; as uricosuric agents, benzbromarone, probenecid or thelike are illustrated; and as urinary alkalinizers, sodium hydrogencarbonate, potassium citrate, sodium citrate or the like areillustrated. These drugs are preferably used for hyperuricemia or gout.

In case of use in combination with drugs other than SGLT2 inhibitors,for example, in the use for diabetes, the combination with at least onemember of the group consisting of an insulin sensitivity enhancer, aglucose absorption inhibitor, a biguanide, an insulin secretionenhancer, an insulin preparation, a glucagon receptor antagonist, aninsulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor,a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1Binhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphataseinhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenaseinhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, aglycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, aglucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist,amylin, an amylin analogue, an amylin agonist and an appetitesuppressant is preferable; the combination with at least one member ofthe group consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer, aninsulin preparation, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogueand an amylin agonist is more preferable; and the combination with atleast one member of the group consisting of an insulin sensitivityenhancer, a glucose absorption inhibitor, a biguanide, an insulinsecretion enhancer and an insulin preparation is most preferable.Similarly, in the use for diabetic complications, the combination withat least one member of the group consisting of an insulin sensitivityenhancer, a glucose absorption inhibitor, a biguanide, an insulinsecretion enhancer, an insulin preparation, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, glycogen synthase kinase-3 inhibitors, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation endproducts formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acidantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, an angiotensin-converting enzymeinhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptorantagonist, an endothelin-converting enzyme inhibitor, an endothelinreceptor antagonist and a diuretic agnet is preferable; and thecombination with at least one member of the group consisting of analdose reductase inhibitor, an angiotensin-converting enzyme inhibitor,a neutral endopeptidase inhibitor and an angiotensin II receptorantagonist is more preferable. Furthermore, in the use for obesity, thecombination with at least one member of the group consisting of aninsulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, an insulin preparation, aglucagon receptor antagonist, an insulin receptor kinase stimulant, atripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor,a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylaseinhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphataseinhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesisinhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor,glucagon-like peptide-1, a glucagon-like peptide-1 analogue, aglucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylinagonist, a β₃-adrenoceptor agonist and an appetite suppressant ispreferable; and the combination with at least one member of the groupconsisting of a β₃-adrenoceptor agonist and an appetite suppressant ismore preferable.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, various dosage forms are useddepending on their uses. As examples of the dosage forms, powders,granules, fine granules, dry sirups, tablets, capsules, injections,solutions, ointments, suppositories, poultices and the like areillustrated, which are orally or parenterally administered.

These pharmaceutical compositions can be prepared by admixing with or bydiluting and dissolving an appropriate pharmaceutical additive such asexcipients, disintegrators, binders, lubricants, diluents, buffers,isotonicities, antiseptics, moistening agents, emulsifiers, dispersingagents, stabilizing agents, dissolving aids and the like, andformulating the mixture in accordance with conventional.

In case of the use of the compound of the present invention incombination with the drugs other than SGLT2 inhibitors, they can beprepared by formulating each active ingredient together or individually.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, the dosage of a compoundrepresented by the above general formula (I) or a pharmaceuticallyacceptable salt thereof as the active ingredient is appropriatelydecided depending on the age, sex, body weight and degree of symptomsand treatment of each patient, which is approximately within the rangeof from 0.1 to 1,000 mg per day per adult human in the case of oraladministration and approximately within the range of from 0.01 to 300 mgper day per adult human in the case of parenteral administration, andthe daily dose can be divided into one to several doses per day andadministered suitably. Also, in case of the use of the compound of thepresent invention in combination with the drugs other than SGLT2inhibitors, the dosage of the compound of the present invention can bedecreased appropriately and occasionally depending on the dosage of thedrugs other than SGLT2 inhibitors.

The present invention is further illustrated in more detail by way ofthe following Reference Examples, Examples and Test Examples. However,the present invention is not limited thereto.

REFERENCE EXAMPLE 11,2-Dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one

To a solution of 4-isopropoxybenzylalcohol (0.34 g) in tetrahydrofuran(6 mL) were added triethylamine (0.28 mL) and methanesulfonyl chloride(0.16 mL), and the mixture was stirred at room temperature for 30minutes. The resulting insoluble material was removed by filtration. Theobtained solution of 4-isopropoxybenzyl methanesulfonate intetrahydrofuran was added to a suspension of sodium hydride (60%, 81 mg)and methyl acetoacetate (0.20 mL) in 1,2-dimethoxyethane (10 mL), andthe mixture was stirred at 80° C. overnight. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andthe resulting mixture was extracted with diethyl ether. The organiclayer was washed with brine and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure, and the residue wasdissolved in toluene (5 mL). Anhydrous hydrazine (0.19 mL) was added tothe solution, and the mixture was stirred at 80° C. overnight. Thesolvent was removed under reduced pressure, and the residue was purifiedby column chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (95mg).

¹H-NMR (DMSO-d₆) δ ppm:

1.22 (6H, d, J=6.0 Hz), 1.99 (3H, s), 3.45 (2H, s), 4.40-4.60 (1H, m),6.65-6.80 (2H, m), 6.95-7.10 (2H, m)

REFERENCE EXAMPLE 21,2-Dihydro-5-methyl-4-[(4-propylphenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-propylbenzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm:

0.75-0.95 (3H, m), 1.45-1.65 (2H, m), 1.99 (3H, s), 2.40-2.55 (2H, m),3.32 (2H, s), 6.95-7.10 (4H, m)

REFERENCE EXAMPLE 31,2-Dihydro-4-[(4-isobutylphenyl)methyl]-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-isobutylbenzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm:

0.83 (6H, d, J=6.6 Hz), 1.70-1.85 (1H, m), 1.99 (3H, s), 2.30-2.45 (2H,m), 3.50 (2H, s), 6.90-7.10 (4H, m)

REFERENCE EXAMPLE 41,2-Dihydro-5-methyl-4-[(4-propoxyphenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-propoxybenzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm:

0.95 (3H, t, J=7.4 Hz), 1.60-1.75 (2H, m), 1.98 (3H, s) 3.46 (2H, s),3.75-3.90 (2H, m), 6.70-6.85 (2H, m), 6.95-7.10 (2H, m)

REFERENCE EXAMPLE 54-[(4-Ethoxyphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-ethoxybenzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm:

1.20-1.35 (3H, m), 1.98 (3H, s), 3.46 (2H, s), 3.85-4.05 (2H, m),6.70-6.85 (2H, m), 6.95-7.10 (2H, m)

REFERENCE EXAMPLE 61,2-Dihydro-5-methyl-4-[(4-trifluoromethylphenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-trifluoro-methylbenzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm:

2.02 (3H, s), 3.64 (2H, s), 7.30-7.45 (2H, m), 7.55-7.70 (2H, m)

REFERENCE EXAMPLE 74-[(4-tert-Butylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-tert-butylbenzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm:

1.24 (9H, s), 2.01 (3H, s), 3.49 (2H, s), 7.00-7.15 (2H, m), 7.15-7.30(2H, m)

REFERENCE EXAMPLE 84-[(4-Butoxyphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-butoxybenzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm:

0.91 (3H, t, J=7.4 Hz), 1.30-1.50 (2H, m), 1.55-1.75 (2H, m), 1.98 (3H,s), 3.46 (2H, s), 3.80-3.95 (2H, m), 6.70-6.85 (2H, m), 6.95-7.10 (2H,m)

REFERENCE EXAMPLE 91,2-Dihydro-5-methyl-4-[(4-methylthiophenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-(methylthio)benzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm:

1.99 (3H, s), 2.42 (3H, s), 3.50 (2H, s), 7.05-7.20 (4H, m)

REFERENCE EXAMPLE 105-Ethyl-1,2-dihydro-4-[(4-methylthiophenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 1 using 4-(methylthio)benzyl alcohol instead of4-isopropoxybenzyl alcohol and using methyl 3-oxopentanoate instead ofmethyl acetoacetate.

¹H-NMR (DMSO-d₆) δ ppm:

1.02 (3H, t, J=7.6 Hz), 2.39 (2H, q, J=7.6 Hz), 2.42 (3H, s), 3.51 (2H,s), 7.05-7.20 (4H, m)

REFERENCE EXAMPLE 111,2-Dihydro-4-[(4-isopropylphenyl)methyl]-5-methyl-3H-pyrazol-3-one

To a suspension of sodium hydride (60%, 40 mg) in 1,2-dimethoxyethane (1mL) were added methyl acetoacetate (0.11mL), 4-isopropylbenzyl chloride(0.17 g) and a catalytic amount of sodium iodide, and the mixture wasstirred at 80° C. overnight. The reaction mixture was poured into asaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with diethyl ether. The organic layer was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was dissolved in toluene(1 mL). Anhydrous hydrazine (0.094 mL) was added to the solution, andthe mixture was stirred at 80° C. overnight. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: dichloromethane/methanol=10/1) togive 1,2-dihydro-4-[(4-isopropylphenyl)methyl]-5-methyl-3H-pyrazol-3-one(0.12 g).

¹H-NMR (DMSO-d₆) δ ppm:

1.16 (6H, d, J=6.9 Hz), 2.01 (3H, s), 2.70-2.90 (1H, m), 3.49 (2H, s),6.95-7.20 (4H, m)

REFERENCE EXAMPLE 124-[(4-Ethylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using 4-ethylbenzyl chloride instead of4-isopropylbenzyl chloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.13 (3H, t, J=7.6 Hz), 2.00 (3H, s), 2.45-2.60 (2H, m), 3.49 (2H, s),7.00-7.15 (4H, m)

REFERENCE EXAMPLE 131,2-Dihydro-5-methyl-4-[(4-methylphenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using 4-methylbenzyl bromide instead of4-isopropylbenzyl chloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.98 (3H, s), 2.23 (3H, s), 3.48 (2H, s), 6.95-7.10 (4H, m)

REFERENCE EXAMPLE 144-Benzyl-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using ethyl trifluoro-acetoacetate instead ofmethyl acetoacetate and using benzyl bromide instead of4-isopropylbenzyl chloride.

¹H-NMR (DMSO-d₆) δ ppm:

3.73 (2H, s), 7.05-7.35 (5H, m), 12.50-13.10 (1H, brs)

REFERENCE EXAMPLE 151,2-Dihydro-4-[(4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using 4-methoxybenzyl bromide instead of4-isopropylbenzyl chloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.99 (3H, s), 3.47 (2H, s), 3.69 (3H, s), 6.75-6.85 (2H, m), 7.00-7.10(2H, m), 8.70-11.70 (2H, br)

REFERENCE EXAMPLE 16 4-Benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using benzyl bromide instead of 4-isopropylbenzylchloride.

¹H-NMR (DMSO-d₆) δ ppm:

2.00 (3H, s), 3.54 (2H, s), 7.05-7.30 (5H, s)

REFERENCE EXAMPLE 174-[(4-Isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-β-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (46mg), acetobromo-α-D-glucose (99 mg) and 4 A molecular sieves intetrahydrofuran (3 mL) was added silver carbonate (66 mg), and themixture was stirred under shading the light at 65° C. overnight. Thereaction mixture was purified by column chromatography on aminopropylsilica gel (eluent: tetrahydrofuran). Further purification bypreparative thin layer chromatography on silica gel (developing solvent:ethyl acetate/hexane=2/1) afforded4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(42 mg).

¹H-NMR (CDCl₃) δ ppm:

1.25-1.35 (6H, m), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.05 (3H,s), 2.10 (3H, s), 3.45-3.65 (2H, m), 3.80-3.90 (1H, m), 4.13 (1H, dd,J=2.3, 12.4 Hz), 4.31 (1H, dd, J=4.0, 12.4 Hz), 4.40-4.55 (1H, m),5.15-5.35 (3H, m), 5.50-5.60 (1H, m), 6.70-6.80 (2H, m), 6.95-7.05 (2H,m).

REFERENCE EXAMPLE 185-Methyl-4-[(4-propylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using1,2-dihydro-5-methyl-4-[(4-propylphenyl)methyl]-3H-pyrazol-3-one insteadof 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

0.91 (3H, t, J=7.3 Hz), 1.50-1.65 (2H, m), 1.86 (3H, s), 2.01 (3H, s),2.03 (3H, s), 2.05 (3H, s), 2.10 (3H, s), 2.45-2.55 (2H, m), 3.55 (1H,d, J=15.8 Hz), 3.63 (1H, d, J=15.8 Hz), 3.80-3.90 (1H, m), 4.13 (1H, dd,J=2.3, 12.4 Hz), 4.30 (1H, dd, J=3.9, 12.4 Hz), 5.15-5.35 (3H, m),5.50-5.60 (1H, m), 7.00-7.20 (4H, m)

REFERENCE EXAMPLE 194-[(4-Isobutylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using1,2-dihydro-4-[(4-isobutylphenyl)methyl]-5-methyl-3H-pyrazoi-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

0.87 (6H, d, J=6.6 Hz), 1.70-1.85 (1H, m), 1.87 (3H, s), 2.01 (3H, s),2.03 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 2.40 (2H, d, J=7.2 Hz), 3.56(1H, d, J=15.8 Hz), 3.63 (1H, d, J=15.8 Hz), 3.80-3.90 (1H, m), 4.14(1H, dd, J=2.3, 12.4 Hz), 4.31 (1H, dd, J=4.0, 12.4 Hz), 5.15-5.35 (3H,m), 5.50-5.60 (1H, m), 6.95-7.10 (4H, m)

REFERENCE EXAMPLE 205-Methyl-4-[(4-propoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using1,2-dihydro-5-methyl-4-[(4-propoxyphenyl)methyl]-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one

¹H-NMR (CDCl₃) δ ppm:

1.01 (3H, t, J=7.4 Hz), 1.70-1.85 (2H, m), 1.89 (3H, s), 2.01 (3H, s),2.03 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 3.53 (1H, d, J=15.7 Hz), 3.59(1H, d, J=15.7 Hz), 3.80-3.95 (3H, m), 4.14 (1H, dd, J=2.3, 12.4 Hz),4.31 (1H, dd, J=4.0, 12.4 Hz), 5.15-5.35 (3H, m), 5.50-5.60 (1H, m),6.70-6.80 (2H, m), 6.95-7.10 (2H, m)

REFERENCE EXAMPLE 214-[(4-Ethoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-[(4-ethoxyphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one insteadof 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.38 (3H, t, J=7.0 Hz), 1.89 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06(3H, s), 2.10 (3H, s), 3.53 (1H, d, J=15.8 Hz), 3.59 (1H, d, J=15.8 Hz),3.80-3.90 (1H, m), 3.98 (2H, q, J=7.0 Hz), 4.13 (1H, dd, J=2.3, 12.4Hz), 4.31 (1H, dd, J=4.0, 12.4), 5.15-5.30 (3H, m), 5.50-5.60 (1H, m),6.70-6.80 (2H, m), 6.95-7.10 (2H, m)

REFERENCE EXAMPLE 225-Methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-trifluoromethylphenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using1,2-dihydro-5-methyl-4-[(4-trifluoromethylphenyl)methyl]-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.85 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.14 (3H, s),3.65 (1H, d, J=15.9 Hz), 3.71 (1H, d, J=15.9 Hz), 3.80-3.90 (1H, m),4.14 (1H, dd, J=2.4, 12.4 Hz), 4.31 (1H, dd, J=4.0, 12.4 Hz), 5.15-5.40(3H, m), 5.55-5.65 (1H, m), 7.20-7.30 (2H, m), 7.45-7.55 (2H, m)

REFERENCE EXAMPLE 234-[(4-tert-Butylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-[(4-tert-butylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.27 (9H, s), 1.84 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s),2.14 (3H, s), 3.56 (1H, d, J=15.8 Hz), 3.64 (1H, d, J=15.8 Hz),3.80-3.90 (1H, m), 4.13 (1H, dd, J=2.3, 12.4 Hz), 4.31 (1H, dd, J=4.0,12.4 Hz), 5.15-5.30 (3H, m), 5.50-5.60 (1H, m), 7.00-7.10 (2H, m),7.20-7.30 (2H, m)

REFERENCE EXAMPLE 244-[(4-Butoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-[(4-butoxyphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one insteadof 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

0.96 (3H, t, J=7.4 Hz), 1.40-1.55 (2H, m), 1.65-1.80 (2H, m), 1.88 (3H,s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 3.52 (1H, d,J=15.8 Hz), 3.59 (1H, d, J=15.8 Hz), 3.80-3.90 (1H, m), 3.91 (2H, t,J=6.5 Hz), 4.13 (1H, dd, J=2.3, 12.4 Hz), 4.31 (1H, dd, J=4.0, 12.4 Hz),5.15-5.30 (3H, m), 5.50-5.60 (1H, m), 6.70-6.80 (2H, m), 6.95-7.10 (2H,m)

REFERENCE EXAMPLE 255-Methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using1,2-dihydro-5-methyl-4-[(4-methylthiophenyl)methyl]-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.07 (3H, s), 2.12 (3H, s),2.44 (3H, s), 3.50-3.65 (2H, m), 3.80-3.90 (1H, m), 4.13 (1H, dd, J=2.4,12.4 Hz), 4.31 (1H, dd, J=4.1, 12.4 Hz), 5.15-5.30 (3H, m), 5.55-5.65(1H, m), 7.00-7.10 (2H, m), 7.10-7.20 (2H, m), 8.65-8.85 (1H, brs)

REFERENCE EXAMPLE 265-Ethyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using5-ethyl-1,2-dihydro-4-[(4-methylthiophenyl)methyl]-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.13 (3H, t, J=7.6 Hz), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06(3H, s), 2.44 (3H, s), 2.45-2.55 (2H, m), 3.50-3.70 (2H, m), 3.80-3.90(1H, m), 4.05-4.20 (1H, m), 4.31 (1H, dd, J=4.0, 12.4 Hz), 5.15-5.35(3H, m), 5.55-5.65 (1H, m), 7.00-7.10 (2H, m), 7.10-7.20 (2H, m),8.80-9.20 (1H, brs)

REFERENCE EXAMPLE 274-[(4-Isopropylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using1,2-dihydro-4-[(4-isopropylphenyl)methyl]-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.20 (6H, d, J=6.9 Hz), 1.85 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06(3H, s), 2.13 (3H, s), 2.75-2.90 (1H, m), 3.56 (1H, d, J=15.8 Hz), 3.63(1H, d, J=15.8 Hz), 3.80-3.90 (1H, m), 4.05-4.20 (1H, m), 4.31 (1H, dd,J=4.0, 12.4 Hz), 5.15-5.35 (3H, m), 5.50-5.60 (1H, m), 7.00-7.15 (4H,m), 8.70-9.30 (1H, brs)

REFERENCE EXAMPLE 284-[(4-Methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

To a solution of1,2-dihydro-4-[(4-methylthiophenyl)-methyl]-5-trifluoromethyl-3H-pyrazol-3-one(2.0 g) in acetonitrile (100 mL) were added acetobromo-α-D-glucose (3.1g) and potassium carbonate (1.1 g), and the mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous sodium hydrogen carbonate solutionand brine and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate 1/1) to give4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole(2.0 g).

¹H-NMR (CDCl₃) δ ppm:

1.91 (3H, s), 2.03 (3H, s), 2.04 (3H, s), 2.09 (3H, s), 2.45 (3H, s),3.73 (2H, s), 3.75-3.90 (1H, m), 4.15-4.35 (2H, m), 5.15-5.65 (4H, m),7.00-7.20 (4H, m)

REFERENCE EXAMPLE 294-Benzyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 28 using4-benzyl-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-one instead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.89 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.08 (3H, s), 3.70-3.90 (3H,m), 4.15-4.30 (2H, m), 5.10-5.50 (4H, m), 7.10-7.30 (5H, m)

REFERENCE EXAMPLE 304-[(4-Methoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 28 using1,2-dihydro-4-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.93 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.09 (3H, s), 3.65-3.75 (2H,m), 3.77 (3H, s), 3.75-3.90 (1H, m), 4.15-4.35 (2H, m), 5.10-5.45 (4H,m), 6.75-6.85 (2H, m), 7.00-7.15 (2H, m)

REFERENCE EXAMPLE 314-[(4-Methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using1,2-dihydro-4-[(4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.89 (3H, s), 2.02 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.10 (3H, s),3.45-3.65 (2H, m), 3.76 (3H, s), 3.80-3.90 (1H, m), 4.11 (1H, dd, J=2.2,12.4 Hz), 4.30 (1H, dd, J=4.0, 12.4 Hz), 5.15-5.35 (3H, m), 5.50-5.60(1H, m), 6.70-6.85 (2H, m), 7.00-7.10 (2H, m)

REFERENCE EXAMPLE 324-Benzyl-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one instead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm:

1.86 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.11 (3H, s),3.59 (1H, d, J=15.8 Hz), 3.66 (1H, d, J=15.8 Hz), 3.80-3.90 (1H, m),4.11 (1H, dd, J=2.3, 12.4 Hz), 4.30 (1H, dd, J=4.0, 12.4 Hz), 5.15-5.30(3H, m), 5.50-5.65 (1H, m), 7.05-7.30 (5H, m), 8.75-9.55 (1H, brs)

REFERENCE EXAMPLE 334-[(4-Methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazole

A suspension of4-[(4-methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(18 mg), potassium carbonate (14 mg) and Iodomethane (4.7 mg) inacetonitrile (2 mL) was stirred at 75° C. overnight. The reactionmixture was filtered through Celite®, and the solvent of the filtratewas removed under reduced pressure. The residue was purified bypreparative thin layer chromatography on silica gel (developing solvent:benzene/acetone=2/1) to give4-[(4-methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazole(4 mg).

¹H-NMR (CDCl₃) δ ppm:

1.90 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.07 (3H, s),3.45-3.60 (2H, m), 3.60 (3H, s), 3.76 (3H, s), 3.80-3.90 (1H, m), 4.13(1H, dd, J=2.4, 12.4 Hz), 4.29 (1H, dd, J=4.1, 12.4 Hz), 5.15-5.30 (3H,m), 5.50-5.60 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m)

REFERENCE EXAMPLE 341-Methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole

A suspension of4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-tri-fluoromethyl-1H-pyrazole(30 mg), potassium carbonate (8.0 mg) and iodomethane (8.2 mg) intetrahydrofuran (1 mL) was stirred at 75° C. overnight. The reactionmixture was filtered through Celite®, and the solvent of the filtratewas removed under reduced pressure. The residue was purified bypreparative thin layer chromatography on silica gel (developing solvent:dichloromethane/ethyl acetate=5/1) to give1-methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole(13 mg).

¹H-NMR (CDCl₃) δ ppm:

1.89 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.07 (3H, s), 2.44 (3H, s),3.65-3.95 (6H, m), 4.14 (1H, dd, J=2.3, 12.4 Hz), 4.29 (1H, dd, J=4.3,12.4 Hz), 5.15-5.35 (3H, m), 5.50-5.65 (1H, m), 7.00-7.20 (4H, m)

REFERENCE EXAMPLE 351-Ethyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 34 using iodoethane instead of iodomethane.

¹H-NMR (CDCl₃) δ ppm:

1.40 (3H, t, J=7.2 Hz), 1.90 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.06(3H, s), 2.44 (3H, s), 3.72 (2H, s), 3.80-3.90 (1H, m), 4.05-4.20 (3H,m), 4.27 (1H, dd, J=4.5, 12.4 Hz), 5.10-5.35 (3H, m), 5.55-5.65 (1H, m),7.00-7.10 (2H, m), 7.10-7.20 (2H, m)

REFERENCE EXAMPLE 364-[(4-Methylthiophenyl)methyl]-1-propyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 34 using 1-iodopropane instead of iodomethane.

¹H-NMR (CDCl₃) δ ppm:

0.92 (3H, t, J=7.4 Hz), 1.75-1.90 (2H, m), 1.89 (3H, s), 2.02 (3H, s),2.04 (3H, s), 2.06 (3H, s), 2.44 (3H, s), 3.72 (2H, s), 3.80-3.90 (1H,m), 3.90-4.05 (2H, m), 4.12 (1H, dd, J=2.3, 12.4 Hz), 4.27 (1H, dd,J=4.5, 12.4 Hz), 5.10-5.35 (3H, m), 5.55-5.65 (1H, m), 7.00-7.10 (2H,m), 7.10-7.20 (2H, m)

REFERENCE EXAMPLE 373-(β-D-Glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole

To a solution of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(61 mg) in ethanol (3 mL) was added 1 mol/L aqueous sodium hydroxidesolution (0.53 mL), and the mixture was stirred at room temperature for2 hours. The solvent was removed under reduced pressure, and the residuewas purified by solid phase extraction on ODS (washing solvent:distilled water, eluent: methanol) to give3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole(39 mg).

¹H-NMR (CD₃OD) δ ppm:

1.26 (6H, d, J=5.9 Hz), 2.05 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H,m), 3.75-3.90 (1H, m), 4.45-4.60 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80(2H, m), 7.00-7.15 (2H, m)

REFERENCE EXAMPLE 383-(β-D-Glucopyranosyloxy)-5-methyl-4-[(4-propylphenyl)-methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using5-methyl-4-[(4-propylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

0.91 (3H, t, J=7.5 Hz), 1.50-1.65 (2H, m), 2.05 (3H, s), 2.45-2.60 (2H,m), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.83 (1H, d, J=11.9 Hz),5.00-5.10 (1H, m), 7.00-7.15 (4H, m)

EXAMPLE 393-(β-D-Glucopyranosyloxy)-4-[(4-isobutylphenyl)methyl]-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-isobutyl-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

0.87 (6H, d, J=6.6 Hz), 1.70-1.90 (1H, m), 2.04 (3H, s), 2.41 (2H, d,J=7.1 Hz), 3.25-3.45 (4H, m), 3.55-3.90 (4H, m), 5.00-5.10 (1H, m),6.95-7.15 (4H, m)

REFERENCE EXAMPLE 403-(β-D-Glucopyranosyloxy)-5-methyl-4-[(4-propoxyphenyl)-methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using5-methyl-4-[(4-propoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.02 (3H, t, J=7.4 Hz), 1.65-1.80 (2H, m), 2.05 (3H, s), (4H, m),3.60-3.75 (3H, m), 3.80-3.90 (3H, m), (1H, m), 6.70-6.85 (2H, m),7.05-7.15 (2H, m)

REFERENCE EXAMPLE 414-[(4-Ethoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-ethoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyioxy)-1H-pyrazoleinstead of4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.34 (3H, t, J=7.0 Hz), 2.05 (3H, s), 3.25-3.45 (4H, m), 3.60-3.75 (3H,m), 3.80-3.90 (1H, m), 3.97 (2H, q, J=7.0 Hz), 5.00-5.10 (1H, m),6.70-6.85 (2H, m), 7.05-7.15 (2H, m)

REFERENCE EXAMPLE 423-(D-D-Glucopyranosyloxy)-5-methyl-4-[(4-trifluoromethyl-phenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-trifluoromethylphenyl)methyl]-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.08 (3H, s), 3.20-3.40 (4H, m), 3.67 (1H, dd, J=5.0, 11.9 Hz),3.75-3.90 (3H, m), 5.00-5.10 (1H, m), 7.30-7.45 (2H, m), 7.45-7.60 (2H,m)

REFERENCE EXAMPLE 434-[(4-tert-Butylphenyl)methyl]-3-(1-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-tert-butylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.28 (9H, s), 2.06 (3H, s), 3.25-3.45 (4H, m), 3.60-3.90 (4H, m),5.00-5.10 (1H, m), 7.05-7.15 (2H, m), 7.20-7.30 (2H, m)

REFERENCE EXAMPLE 444-[(4-Butoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-butoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

0.97 (3H, t, J=7.4 Hz), 1.40-1.55 (2H, m), 1.65-1.80 (2H, m), 2.05 (3H,s), 3.30-3.45 (4H, m), 3.60-3.75 (3H, m), 3.83 (1H, d, J=12.0 Hz), 3.91(2H, t, J=6.4 Hz), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.05-7.15 (2H,m)

REFERENCE EXAMPLE 453-(β-D-Glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)-methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using5-methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.06 (3H, s), 2.42 (3H, s), 3.20-3.45 (4H, m), 3.55-3.75 (3H, m),3.80-3.90 (1H, m), 5.00-5.10 (1H, m), 7.05-7.20 (4H, m)

REFERENCE EXAMPLE 465-Ethyl-3-(β-D-glucopyranosyloxy)-4-[(4-methylthiophenyl)-methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using5-ethyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.06 (3H, t, J=7.6 Hz), 2.42 (3H, s), 2.47 (2H, q, J=7.6 Hz), 3.25-3.45(4H, m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m), 5.00-5.10 (1H, m),7.10-7.20 (4H, m)

REFERENCE EXAMPLE 473-(β-D-Glucopyranosyloxy)-4-[(4-isopropylphenyl)methyl]-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-isopropyl-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.20 (6H, d, J=6.9 Hz), 2.05 (3H, s), 2.75-2.90 (1H, m), 3.25-3.45 (4H,m), 3.55-3.90 (4H, m), 5.00-5.10 (1H, m), 7.00-7.15 (4H, m)

REFERENCE EXAMPLE 483-(β-D-Glucopyranosyloxy)-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.42 (3H, s), 3.25-3.50 (4H, m), 3.69 (1H, dd, J=4.9, 12.0 Hz),3.75-3.90 (3H, m), 4.90-5.10 (1H, m), 7.10-7.20 (4H, m)

REFERENCE EXAMPLE 494-Benzyl-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-benzyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoro-methyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

3.25-3.45 (4H, m), 3.67 (1H, dd, J=5.3, 12.0 Hz), 3.80-3.95 (3H, m),4.97 (1H, d, J=7.4 Hz), 7.05-7.25 (5H, m)

REFERENCE EXAMPLE 503-(β-D-Glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-methoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

3.25-3.45 (4H, m), 3.67 (1H, d, J=5.4, 12.1 Hz), 3.73 (3H, s), 3.75-3.90(3H, m), 4.90-5.00 (1H, m), 6.70-6.85 (2H, m), 7.05-7.15 (2H, m)

REFERENCE EXAMPLE 513-(β-D-Glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.04 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.73 (3H, s),3.80-3.90 (1H, m), 5.00-5.10 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H,m)

REFERENCE EXAMPLE 524-Benzyl-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.05 (3H, s), 3.25-3.45 (4H, m), 3.60-3.90 (4H, m), 5.00-5.10 (1H, m),7.05-7.25 (5H, m)

REFERENCE EXAMPLE 533-(β-D-Glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-1,5-dimethylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.06 (3H, s), 3.25-3.45 (4H, m), 3.55-3.70 (6H, m), 3.73 (3H, s),3.75-3.90 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.05-7.15 (2H,m)

REFERENCE EXAMPLE 543-(β-D-Glucopyranosyloxy)-1-methyl-4-[(4-methylthiophenyl)-methyl]-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using1-methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.42 (3H, s), 3.30-3.50 (4H, m), 3.69 (1H, dd, J=4.7, 12.0 Hz),3.75-3.90 (6H, m), 5.25-5.35 (1H, m), 7.05-7.20 (4H, m)

REFERENCE EXAMPLE 551-Ethyl-3-(β-D-glucopyranosyloxy)-4-[(4-methylthiophenyl)-methyl]-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using1-ethyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.38 (3H, t, J=7.1 Hz), 2.42 (3H, s), 3.30-3.50 (4H, m), 3.60-3.75 (1H,m), 3.75-3.90 (3H, m), 4.14 (2H, q, J=7.1 Hz), 5.25-5.35 (1H, m),7.05-7.20 (4H, m)

REFERENCE EXAMPLE 563-(β-D-Glucopyranosyloxy)-4-[(4-methylthiophenyl)methyl]-1-propyl-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 37 using4-[(4-methylthio-phenyl)methyl]-1-propyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

0.90 (3H, t, J=7.4 Hz), 1.75-1.90 (2H, m), 2.42 (3H, s), 3.30-3.50 (4H,m), 3.69 (1H, dd, J=4.9, 12.0 Hz), 3.75-3.90 (3H, m), 4.00-4.10 (2H, m),5.25-5.35 (1H, m), 7.05-7.20 (4H, m)

REFERENCE EXAMPLE 573-(β-D-Glucopyranosyloxy)-5-methyl-4-[(4-methylphenyl)-methyl]-1H-pyrazole

5-Methyl-4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazolewas prepared in a similar manner to that described in Reference Example17 using1,2-dihydro-5-methyl-4-[(4-methylphenyl)methyl]-3H-pyrazol-3-one insteadof 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Reference Example 37 using5-methyl-4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.04 (3H, s), 2.26 (3H, s), 3.25-3.45 (4H, m), 3.55-3.90 (4H, m),5.00-5.10 (1H, m), 6.95-7.15 (4H, m)

REFERENCE EXAMPLE 584-[(4-Ethylphenyl)methyl]-3-(O-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

4-[(4-Ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazolewas prepared in a similar manner to that described in Reference Example17 using 4-[(4-ethylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Reference Example 37 using4-[(4-ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.6 Hz), 2.04 (3H, s), 2.57 (2H, q, J=7.6 Hz), 3.25-3.45(4H, m), 3.55-3.90 (4H, m), 5.00-5.10 (1H, m), 6.95-7.20 (4H, m)

REFERENCE EXAMPLE 593-(β-D-Glucopyranosyloxy)-4-[(4-methylphenyl)methyl]-5-trifluoromethyl-1H-pyrazole

4-[(4-Methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Reference Example28 using1,2-dihydro-4-[(4-methylphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Reference Example 37 using4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

2.25 (3H, s), 3.20-3.45 (4H, m), 3.55-3.70 (1H, m), 3.70-3.90 (3H, m),4.80-4.95 (1H, m), 6.90-7.15 (4H, m)

REFERENCE EXAMPLE 604-[(4-Ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

4-[(4-Ethylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Reference Example28 using4-[(4-ethylphenyl)methyl]-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Reference Example 37 using4-[(4-ethyl-phenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.6 Hz), 2.50-2.60 (2H, m), 3.15-3.40 (4H, m), 3.55-3.65(1H, m), 3.70-3.90 (3H, m), 4.80-4.95 (1H, m), 6.95-7.15 (4H, m)

REFERENCE EXAMPLE 613-(β-D-Glucopyranosyloxy)-4-[(4-isopropylphenyl)methyl]-5-trifluoromethyl-1H-pyrazole

4-[(4-Isopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Reference Example28 using1,2-dihydro-4-[(4-isopropylphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Reference Example 37 using4-[(4-isopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

1.20 (6H, d, J=6.9 Hz), 2.75-2.85 (1H, m), 3.15-3.40 (4H, m), 3.55-3.65(1H, m), 3.70-3.90 (3H, m), 4.80-4.95 (1H, m), 7.00-7.15 (4H, m)

REFERENCE EXAMPLE 624-[(4-Chlorophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

4-[(4-Chlorophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Reference Example28 using4-[(4-chlorophenyl)methyl]-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Reference Example 37 using4-[(4-chlorophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

3.20-3.40 (4H, m), 3.55-3.70 (1H, m), 3.75-3.90 (3H, m), 4.80-4.95 (1H,m), 7.10-7.25 (4H, m)

REFERENCE EXAMPLE 633-(β-D-Glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1-propylpyrazole

To a suspension of3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole(50 mg) and cesium carbonate (0.20 g) in N,N-dimethylformamide (1 mL)was added 1-iodopropane (0.036 mL) at 50° C., and the mixture wasstirred overnight. Water was added to the reaction mixture, and theresulting mixture was purified by solid phase extraction on ODS (washingsolvent: distilled water, eluent: methanol). The resulting semi-purifiedmaterial was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=8/1) to give3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1-propylpyrazole(28 mg).

¹H-NMR (CD₃OD) δ ppm:

0.87 (3H, t, J=7.4 Hz), 1.26 (6H, d, J=6.0 Hz), 1.65-1.80 (2H, m), 2.07(3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.75-3.95 (3H, m),4.40-4.60 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H,m)

REFERENCE EXAMPLE 641-Ethyl-3-(β-D-glucopyranosyloxy)-4-[(4-isopropylphenyl)-methyl]-5-methylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using iodoethane instead of 1-iodpropane.

¹H-NMR (CD₃OD) δ ppm:

1.26 (6H, d, J=6.0 Hz), 1.29 (3H, t, J=7.2 Hz), 2.08 (3H, s), 3.25-3.45(4H, m), 3.55-3.75 (3H, m), 3.75-3.90 (1H, m), 3.96 (2H, q, J=7.2 Hz),4.40-4.60 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H,m)

REFERENCE EXAMPLE 651-Ethyl-3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)-methyl]-5-methylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazoleand using iodoethane instead of 1-iodpropane.

¹H-NMR (CD₃OD) δ ppm:

1.29 (3H, t, J=7.1 Hz), 2.07 (3H, s), 3.20-3.45 (4H, m), 3.55-3.75 (6H,m), 3.82 (1H, dd, J=2.0, 12.0 Hz), 3.90-4.05 (2H, m), 5.00-5.10 (1H, m),6.70-6.85 (2H, m), 7.05-7.15 (2H, m)

REFERENCE EXAMPLE 663-(β-D-Glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1-propylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

0.87 (3H, t, J=7.5 Hz), 1.65-1.80 (2H, m), 2.07 (3H, s), 3.35-3.45 (4H,m), 3.60-3.75 (3H, m), 3.73 (3H, s), 3.75-3.85 (1H, m), 3.85-3.95 (2H,m), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.00-7.15 (2H, m)

REFERENCE EXAMPLE 671-Ethyl-4-[(4-ethoxyphenyl)methyl]-3-(β-D-glucopyranosyl-oxy)-5-methylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using4-[(4-ethoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazoleand using iodoethane instead of 1-iodopropane.

¹H-NMR (CD₃OD) δ ppm:

1.28 (3H, t, J=7.4 Hz), 1.34 (3H, t, J=7.2 Hz), 2.07 (3H, s), 3.25-3.45(4H, m), 3.55-3.75 (3H, m), 3.75-3.85 (1H, m), 3.90-4.00 (4H, m),5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.00-7.15 (2H, m)

REFERENCE EXAMPLE 684-[(4-Ethoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1-propylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using4-[(4-ethoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazoleinstead of3-(D-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

0.87 (3H, t, J=7.6 Hz), 1.34 (3H, t, J=7.1 Hz), 1.65-1.80 (2H, m), 2.07(3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.81 (1H, dd, J=2.1, 12.1Hz), 3.85-4.05 (4H, m), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.00-7.15(2H, m)

REFERENCE EXAMPLE 691-Ethyl-4-[(4-ethylphenyl)methyl]-3-(O-D-glucopyranosyl-oxy)-5-methylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazoleand using iodoethane instead of 1-iodopropane.

¹H-NMR (CD₃OD) δ ppm:

1.17 (3H, t, J=7.6 Hz), 1.28 (3H, t, J=7.2 Hz), 2.06 (3H, s), 2.56 (2H,q, J=7.6 Hz), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.75-3.85 (1H, m),3.90-4.00 (2H, m), 5.00-5.10 (1H, m), 7.00-7.15 (4H, m)

REFERENCE EXAMPLE 704-[(4-Ethylphenyl)methyl]-3-(D-D-glucopyranosyloxy)-5-methyl-1-propylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm:

0.87 (3H, t, J=7.4 Hz), 1.17 (3H, t, J=7.6 Hz), 1.65-1.80 (2H, m), 2.06(3H, s), 2.56 (2H, q, J=7.6 Hz), 3.25-3.45 (4H, m), 3.60-3.95 (6H, m),5.00-5.10 (1H, m), 7.00-7.15 (4H, m)

REFERENCE EXAMPLE 711-Butyl-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)-methyl]-5-methylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using 1-bromobutane instead of 1-iodpropane.

¹H-NMR (CD₃OD) δ ppm:

0.92 (3H, t, J=7.4 Hz), 1.20-1.40 (8H, m), 1.60-1.75 (2H, m), 2.07 (3H,s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.81 (1H, dd, J=2.1, 12.0 Hz),3.91 (2H, t, J=7.2 Hz), 4.45-4.55 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80(2H, m), 7.00-7.10 (2H, m)

REFERENCE EXAMPLE 723-(β-D-Glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using 2-bromopropane instead of 1-iodopropane.

¹H-NMR (CD₃OD) δ ppm:

1.26 (6H, d, J=6.0 Hz), 1.30-1.40 (6H, m), 2.08 (3H, s), 3.15-3.45 (4H,m), 3.55-3.75 (3H, m), 3.78 (1H, dd, J=2.3, 12.0 Hz), 4.35-4.45 (1H, m),4.45-4.55 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H,m)

REFERENCE EXAMPLE 734-[(4-Ethylthiophenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

To a solution of 4-ethylthiobenzyl alcohol (8.3 g) and triethylamine(6.9 mL) in tetrahydrofuran (200 mL) was added methanesulfonyl chloride(3.8 mL) at 0° C., and the mixture was stirred for 1 hour. Insolublematerial was removed by filtration. The obtained solution of4-ethylthiobenzyl methanesulfonate in tetrahydrofuran was added to asuspension of sodium hydride (60%, 2.2 g) and methyl acetoacetate (5.3mL) in 1,2-dimethoxyethane (200 mL), and the mixture was stirred at 80°C. overnight. A saturated aqueous sodium hydrogen carbonate solution wasadded to the reaction mixture, and the resulting mixture was extractedwith diethyl ether. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. To a solution of the residue in toluene (150 mL) was addedhydrazine monohydrate (7.2 mL), and the mixture was stirred at 80° C.for 1 hour. The reaction mixture was cooled to 0° C. and stirred foradditional 1 hour. The resulting precipitates were collected byfiltration and washed with water and hexane to give4-[(4-ethylthiophenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.5g).

¹H-NMR (DMSO-d₆) δ ppm:

1.19 (3H, t, J=7.3 Hz), 2.00 (3H, s), 2.90 (2H, q, J=7.3 Hz), 3.51 (2H,s), 7.05-7.15 (2H, m), 7.15-7.25 (2H, m)

REFERENCE EXAMPLE 744-[(4-Ethylthiophenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of4-[(4-ethylthiophenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.6g) and acetobromo-α-D-glucose (2.9 g) in tetrahydrofuran (30 mL) wasadded silver carbonate (2.1 g), and the mixture was stirred undershading the light at 60° C. overnight. The reaction mixture was purifiedby column chromatography on aminopropyl silica gel (eluent:tetrahydrofuran) and further column chromatography on silica gel(eluent: hexane/ethyl acetate=1/3) to give4-[(4-ethyl-thiophenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(1.4 g).

¹H-NMR (CDCl₃) δ ppm:

1.28 (3H, t, J=7.4 Hz), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06(3H, s), 2.11 (3H, s), 2.89 (2H, q, J=7.4 Hz), 3.56 (1H, d, J=15.9 Hz),3.62 (1H, d, J=15.9 Hz), 3.80-3.90 (1H, m), 4.13 (1H, dd, J=2.3, 12.6Hz), 4.31 (1H, dd, J=3.9, 12.6 Hz), 5.15-5.35 (3H, m), 5.55-5.65 (1H,m), 7.00-7.10 (2H, m), 7.15-7.25 (2H, m), 8.79 (1H, brs)

REFERENCE EXAMPLE 754-[(4-Ethylthiophenyl)methyl]-3-(D-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

To a solution of4-[(4-ethylthiophenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(1.3 g) in methanol (10 mL) was added sodium methoxide (28% methanolsolution, 0.13 mL), and the mixture was stirred at room temperature for1 hour. The reaction mixture was concentrated under reduced pressure,and the residue was purified by column chromatography on silica gel(eluent: dichloromethane/methanol=5/1) to give4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole(0.87 g).

¹H-NMR (CD₃OD) δ ppm:

1.24 (3H, t, J=7.3 Hz), 2.06 (3H, s), 2.88 (2H, q, J=7.3 Hz), 3.30-3.45(4H, m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m), 5.00-5.10 (1H, m),7.10-7.30 (4H, m)

REFERENCE EXAMPLE 761-(Benzyloxycarbonyl)-3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methylpyrazole

To a solution of3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole(1.3 g) in tetrahydrofuran (30 mL) was addedN-(benzyloxycarbonyloxy)-succinimide (1.6 g), and the mixture was heatedunder reflux overnight. The reaction mixture was concentrated underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: dichloromethane/methanol=10/1) to give1-(benzyloxycarbonyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole(1.3 g).

¹H-NMR (CDCl₃) δ ppm:

1.27 (6H, d, J=6.3 Hz), 2.35 (3H, s), 3.45-3.70 (6H, m), 3.76 (1H, dd,J=4.5, 12.0 Hz), 3.85 (1H, dd, J=2.8, 12.0 Hz), 4.40-4.50 (1H, m),5.30-5.40 (2H, m), 5.48 (1H, d, J=8.0 Hz), 6.70-6.80 (2H, m), 6.95-7.05(2H, m), 7.25-7.50 (5H, m)

REFERENCE EXAMPLE 771-(Benzyloxycarbonyl)-3-(6-O-ethoxycarbonyl-β-D-gluco-pyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-pyrazole

To a solution of1-(benzyloxycarbonyl)-3-(β-D-gluco-pyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-pyrazole(0.20 g) in 2,4,6-trimethylpyridine (4 mL) was added ethyl chloroformate(0.092 mL), and the mixture was stirred at room temperature for 1 day.To the reaction mixture were added water and citric acid monohydrate,and the resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water, dried over anhydrous magnesium sulfate, andthe solvent was removed under reduced pressure. The residue was purifiedby column chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give1-(benzyloxy-carbonyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole(0.17 g).

¹H-NMR (CD₃OD) δ ppm:

1.19 (3H, t, J=7.1 Hz), 1.26 (6H, d, J=6.0 Hz), 2.36 (3H, s), 3.30-3.50(3H, m), 3.50-3.75 (3H, m), 4.10 (2H, q, J=7.1 Hz), 4.25-4.35 (1H, m),4.35-4.45 (1H, m), 4.45-4.60 (1H, m), 5.35-5.45 (2H, m), 5.45-5.60 (1H,m), 6.70-6.85 (2H, m), 7.00-7.15 (2H, m), 7.30-7.55 (5H, m)

REFERENCE EXAMPLE 781-(Benzyloxycarbonyl)-4-[(4-isopropoxyphenyl)methyl]-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-5-methylpyrazole

The title compound was prepared in a similar manner to that described inReference Example 77 using methyl chloroformate instead of ethylchloroformate.

¹H-NMR (CDCl₃) δ ppm:

1.30 (6H, d, J=6.4 Hz), 2.43 (3H, s), 3.45-3.70 (6H, m), 3.78 (3H, s),4.39 (1H, dd, J=2.2, 11.8 Hz), 4.40-4.55 (2H, m), 5.38 (2H, s),5.40-5.50 (1H, m), 6.70-6.85 (2H, m), 7.00-7.10 (2H, m), 7.30-7.50 (5H,m)

EXAMPLE 13-(6-O-Ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole

To a solution of3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole(0.10 g) in 2,4,6-trimethylpyridine (1 mL) was added ethyl chloroformate(0.072 g), and the mixture was stirred at room temperature overnight. Tothe reaction mixture were added citric acid monohydrate (3.3 g) andwater, and the resulting mixture was purified by ODS solid phaseextraction (washing solvent: distilled water, eluent: methanol). Furtherpurification by column chromatography on silica gel (eluent:dichloromethane/methanol=10/1) and recrystallization (recrystallizationsolvent: ethyl acetate/hexane=⅓) afforded3-(6-O-ethoxy-carbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole(0.084 g).

¹H-NMR (CD₃OD) δ ppm:

1.23 (3H, t, J=7.0 Hz), 1.26 (6H, d, J=5.8 Hz), 1.30-1.40 (6H, m), 2.07(3H, s), 3.25-3.45 (4H, m), 3.60-3.70 (2H, m), (2H, q, J=77.0 Hz), 4.21(1H, dd, J=5.4, 11.6 Hz), 4.34 (1H, dd, J=11.7, 11.6 Hz), 4.35-4.45 (1H,m), 4.45-4.55 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10(2H, m)

EXAMPLES 2-14

The compounds listed in Table 1 were prepared from the correspondingstarting material in a similar manner to that described in Example 1.

TABLE 1 Example R R² Q 2 Methyl Methoxy Methyl 3 Methyl MethylthioTrifluoromethyl 4 Ethyl Methylthio Trifluoromethyl 5 Propyl MethylthioTrifluoromethyl 6 Propyl Isopropoxy Methyl 7 Ethyl Isopropoxy Methyl 8Ethyl Methoxy Methyl 9 Propyl Methoxy Methyl 10 Ethyl Ethoxy Methyl 11Propyl Ethoxy Methyl 12 Ethyl Ethyl Methyl 13 Propyl Ethyl Methyl 14Butyl Isopropoxy Methyl

EXAMPLE 154-[(4-Isopropoxyphenyl)methyl]-1-isopropyl-3-(6-O-methoxy-carbonyl-β-D-glucopyranosyloxy)-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 1 using methyl chloroformate instead of ethyl chloroformate.

¹H-NMR (CD₃OD) δ ppm:

1.26 (6H, d, J=6.1 Hz), 1.30-1.40 (6H, m), 2.07 (3H, s), 3.25-3.45 (4H,m), 3.60-3.70 (2H, m), 3.71 (3H, s), 4.22 (1H, dd, J=5.2, 11.7 Hz), 4.35(1H, dd, J=2.1, 11.7 Hz), 4.35-4.45 (1H, m), 4.45-4.60 (1H, m),5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m)

EXAMPLE 163-(6-O-Isobutyloxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 1 using isobutyl chloroformate instead of ethyl chloroformate.

¹H-NMR (CD₃OD) δ ppm:

0.90 (6H, d, J=6.7 Hz), 1.26 (6H, d, J=5.9 Hz), 1.30-1.40 (6H, m),1.80-2.00 (1H, m), 2.07 (3H, s), 3.25-3.50 (4H, m), 3.60-3.70 (2H, m),3.80-3.90 (2H, m), 4.21 (1H, dd, J=5.2, 11.5 Hz), 4.36 (1H, dd, J=1.8,11.5 Hz), 4.35-4.45 (1H, m), 4.45-4.55 (1H, m), 5.00-5.10 (1H, m),6.70-6.80 (2H, m), 7.00-7.10 (2H, m)

EXAMPLE 174-[(4-Isopropoxyphenyl)methyl]-1-isopropyl-5-methyl-3-(6-O-propionyl-β-D-glucopyranosyloxy)pyrazole

To a solution of3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole(0.10 g) in 2,4,6-trimethylpyridine (1 mL) was added propionyl chloride(0.072 g) at 0° C., and the mixture was stirred for hours. To thereaction mixture were added citric acid monohydrate (3.3 g) and water,and the resulting mixture was purified by ODS solid phase extraction(washing solvent: distilled water, eluent: methanol). Furtherpurification by column chromatography on silica gel (eluent:dichloromethane/methanol=10/1) afforded4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methyl-3-(6-O-propionyl-β-D-glucopyranosyloxy)pyrazole(0.074 g)

¹H-NMR (CD₃OD) δ ppm:

1.05 (3H, t, J=7.5 Hz), 1.26 (6H, d, J=5.9 Hz), 1.30-1.40 (6H, m), 2.07(3H, s), 2.27 (2H, q, J=7.5 Hz), 3.25-3.45 (4H, m), 3.60-3.70 (2H, m),4.18 (1H, dd, J=5.6, 11.8 Hz), 4.30 (1H, dd, J=2.2, 11.8 Hz), 4.35-4.45(1H, m), 4.45-4.55 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m),7.00-7.10 (2H, m)

EXAMPLE 183-(6-O-Acetyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxy-phenyl)methyl]-1-isopropyl-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 17 using acetyl chloride instead of propionyl chloride.

¹H-NMR (CD₃OD) δ ppm:

1.26 (6H, d, J=6.4 Hz), 1.30-1.40 (6H, m), 1.98 (3H, s), 2.08 (3H, s),3.25-3.45 (4H, m), 3.60-3.70 (2H, m), 4.16 (1H, dd, J=5.6, 11.8 Hz),4.29 (1H, dd, J=2.0, 11.8 Hz), 4.35-4.55 (2H, m), 5.00-5.10 (1H, m),6.70-7.80 (2H, m), 7.00-7.10 (2H, m)

EXAMPLE 193-(6-O-Butyryl-β-D-glucopyranosyloxy)-4-[(4-isopropoxy-phenyl)methyl]-1-isopropyl-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 17 using butyryl chloride instead of propionyl chloride.

¹H-NMR (CD₃OD) δ ppm:

0.88 (3H, t, J=7.4 Hz), 1.26 (6H, d, J=6.0 Hz), 1.30-1.40 (6H, m),1.50-1.65 (2H, m), 2.07 (3H, s), 2.15-2.30 (2H, m), 3.25-3.50 (4H, m),3.60-3.70 (2H, m), 4.17 (1H, dd, J=5.7, 11.9 Hz), 4.31 (1H, dd, J=2.0,11.9 Hz), 4.30-4.55 (2H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m),7.00-7.10 (2H, m)

EXAMPLE 204-[(4-Isopropoxyphenyl)methyl]-1-isopropyl-5-methyl-3-(6-O-pivaroyl-β-D-glucopyranosyloxy)pyrazole

The title compound was prepared in a similar manner to that described inExample 17 using pivaloyl chloride instead of propionyl chloride.

¹H-NMR (CD₃OD) δ ppm:

1.10 (9H, s), 1.26 (6H, d, J=6.1 Hz), 1.30-1.40 (6H, m), 2.06 (3H, s),3.30-3.45 (4H, m), 3.60-3.70 (2H, m), 4.16 (1H, dd, J=5.8, 11.7 Hz),4.30 (1H, dd, J=2.0, 11.7 Hz), 4.30-4.55 (2H, m), 5.05-5.15 (1H, m),6.70-6.80 (2H, m), 7.00-7.10 (2H, m)

EXAMPLE 211-Ethoxycarbonyl-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyl-oxy)-4-[(4-ethylthiophenyl)methyl]-5-methylpyrazole

To a solution of4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole(0.03 g) in 2,4,6-trimethylpyridine (0.5 mL) was added ethylchloroformate (0.021 mL), and the mixture was stirred at roomtemperature overnight. To the reaction mixture was added 10% aqueouscitric acid solution, and the resulting mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was removed under reduced pressure. The residue waspurified by preparative thin layer chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give1-ethoxycarbonyl-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyl-oxy)-4-[(4-ethylthiophenyl)methyl]-5-methylpyrazole(0.023 g).

¹H-NMR (CD₃OD) δ ppm:

1.15-1.30 (6H, m), 1.39 (3H, t, J=7.1 Hz), 2.37 (3H, s), 2.87 (2H, q,J=7.3 Hz), 3.35-3.50 (3H, m), 3.60-3.80 (3H, m), 4.12 (2H, q, J=7.1 Hz),4.29 (1H, dd, J=5.3, 11.9 Hz), 4.35-4.50 (3H, m), 5.50-5.60 (1H, m),7.10-7.25 (4H, m)

EXAMPLES 22-43

The compounds listed in Table 2 were prepared from the correspondingstarting material in a similar manner to that

described in Example 21.

TABLE 2 Example R R² Q 22 Ethoxycarbonyl Isopropoxy Methyl 23Ethoxycarbonyl Propyl Methyl 24 Ethoxycarbonyl Isobutyl Methyl 25Ethoxycarbonyl Propoxy Methyl 26 Ethoxycarbonyl Ethoxy Methyl 27Ethoxycarbonyl Trifluoromethyl Methyl 28 Ethoxycarbonyl tert-ButylMethyl 29 Ethoxycarbonyl Butoxy Methyl 30 Ethoxycarbonyl MethylthioMethyl 31 Ethoxycarbonyl Methylthio Ethyl 32 Ethoxycarbonyl IsopropylMethyl 33 Ethoxycarbonyl Methylthio Trifluoromethyl 34 EthoxycarbonylHydrogen Trifluoromethyl 35 Ethoxycarbonyl Methoxy Trifluoromethyl 36Ethoxycarbonyl Methoxy Methyl 37 Ethoxycarbonyl Hydrogen Methyl 38Ethoxycarbonyl Methyl Methyl 39 Ethoxycarbonyl Ethyl Methyl 40Ethoxycarbonyl Methyl Trifluoromethyl 41 Ethoxycarbonyl EthylTrifluoromethyl 42 Ethoxycarbonyl Isopropyl Trifluoromethyl 43Ethoxycarbonyl Chlorine Trifluoromethyl

EXAMPLE 443-(6-O-Ethoxycarbonyl-β-D-glucopyranosyloxy)-1-(ethoxy-carbonyloxymethyl)-4-[(4-methylthiophenyl)methyl]-5-methyl-pyrazole

To a solution of3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole(0.11 g) in water (0.5 mL) and ethanol (0.1 mL) was added formaldehyde(37% aqueous solution, 0.068 mL), and the mixture was stirred at 40° C.for 3 days. To the reaction mixture were added tetrahydrofuran andanhydrous magnesium sulfate, and the resulting insoluble material wasremoved by filtration.

The solvent of the filtrate was removed under reduced pressure. Theresidue was dissolved in 2,4,6-trimethylpyridine (1 mL). Ethylchloroformate (0.099 g) was added to the solution, and the mixture wasstirred at room temperature overnight. To the reaction mixture wereadded citric acid monohydrate (4 g) and water, and the resulting mixturewas purified by ODS solid phase extraction (washing solvent: 10% aqueouscitric acid solution, distilled water, eluent: methanol). Furtherpurification by column chromatography on silica gel (eluent:dichloromethane/methanol=15/1) afforded3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-1-(ethoxycarbonyloxymethyl)-4-[(4-methylthiophenyl)methyl]-5-methylpyrazole(0.058 g).

¹H-NMR (CD₃OD) δ ppm:

1.23 (3H, t, J=7.1 Hz), 1.26 (3H, t, J=7.1 Hz), 2.18 (3H, s), 2.42 (3H,s), 3.30-3.45 (3H, m), 3.50-3.60 (1H, m), 3.63 (1H, d, J=16.0 Hz), 3.70(1H, d, J=16.0 Hz), 4.13 (2H, q, J=7.1 Hz), 4.18 (2H, q, J=7.1 Hz), 4.28(1H, dd, J=4.8, 11.7 Hz), 4.39 (1H, dd, J=2.0, 11.7 Hz), 5.25-5.35 (1H,m), 5.80-5.95 (2H, m), 7.10-7.20 (4H, m)

EXAMPLE 451-Acetyl-4-[(4-ethylthiophenyl)methyl]-3-(β-D-gluco-pyranosyloxy)-5-methylpyrazole

To a solution of4-[(4-ethylthiophenyl)methyl]-3-(D-D-glucopyranosyloxy)-5-methyl-1H-pyrazole(0.41 g) in tetra-hydrofuran (10 mL) were added acetic acid (0.11mL) andacetic anhydride (0.18 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and diethyl ether was added to the residue. Theresulting precipitated crystal was collected by filtration to give1-acetyl-4-[(4-ethylthiophenyl)methyl]-3-(O-D-glucopyranosyloxy)-5-methylpyrazole(0.36 g).

¹H-NMR (CD₃OD) δ ppm: 1.24 (3H, t, J=7.3 Hz), 2.43 (3H, s), 2.54 (3H,s), 2.89 (2H, q, J=7.3 Hz), 3.30-3.50 (4H, m), 3.60-3.75 (3H, m),3.80-3.90 (1H, m), 5.45-5.55 (1H, m), 7.10-7.30 (4H, m)

EXAMPLE 461-Acetyl-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-ethylthiophenyl)methyl]-5-methylpyrazole

To a solution of1-acetyl-4-[(4-ethylthiophenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole(0.03 g) in 2,4,6-trimethylpyridine (0.5 mL) was added ethylchloro-formate (0.012 mL), and the mixture was stirred at roomtemperature overnight. To the reaction mixture was added 10% aqueouscitric acid solution (5 mL), and the resulting mixture was stirred atroom temperature overnight. The resulting precipitatse were collected byfiltration and washed with 10% aqueous citric acid solution and water togive1-acetyl-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-ethylthiophenyl)methyl]-5-methylpyrazole(0.020 g).

¹H-NMR (CD₃OD) δ ppm:

1.20 (3H, t, J=7.2 Hz), 1.24 (3H, t, J=7.4 Hz), 2.41 (3H, s), 2.55 (3H,s), 2.88 (2H, q, J=7.4 Hz), 3.30-3.40 (1H, m), 3.40-3.50 (2H, m),3.50-3.65 (1H, m), 3.65 (1H, d, J=15.8 Hz), 3.72 (1H, d, J=15.8 Hz),4.05-4.15 (2H, m), 4.27 (1H, dd, J=6.3, 11.7 Hz), 4.42 (1H, dd, J=2.0,11.7 Hz), 5.40-5.55 (1H, m), 7.10-7.30 (4H, m)

EXAMPLE 473-(6-O-Ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole

To a solution of1-(benzyloxycarbonyl)-3-(6-O-ethoxy-carbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)-methyl]-5-methylpyrazole(0.17 g) in tetrahydrofuran (4 mL) was added 10% palladium-carbonpowder, and the mixture was stirred under hydrogen atmosphere at roomtemperature for 3 hours. The resulting insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: dichloromethane/methanol=10/1) to give3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxy-phenyl)methyl]-5-methyl-1H-pyrazole(0.10 g).

¹H-NMR (CD₃OD) δ ppm:

1.23 (3H, t, J=7.1 Hz), 1.26 (6H, d, J=6.0 Hz), 2.04 (3H, s), 3.30-3.55(4H, m), 3.61 (1H, d, J=15.9 Hz), 3.67 (1H, d, J=15.9 Hz), 4.12 (2H, q,J=7.1 Hz), 4.27 (1H, dd, J=4.9, 11.7 Hz), 4.38 (1H, dd, J=2.0, 11.7 Hz),4.45-4.60 (1H, m), 5.10-5.20 (1H, m), 6.70-6.80 (2H, m), 7.00-7.15 (2H,m)

EXAMPLE 484-[(4-Isopropoxyphenyl)methyl]-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 47 using1-(benzyloxycarbonyl)-4-[(4-isopropoxyphenyl)methyl]-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-5-methylpyrazoleinstead of1-(benzyloxycarbonyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole.

¹H-NMR (CD30D) δ ppm:

1.26 (6H, d, J=5.9 Hz), 2.04 (3H, s), 3.30-3.55 (4H, m), 3.61 (1H, d,J=15.9 Hz), 3.67 (1H, d, J=15.9 Hz), 3.72 (3H, s), 4.28 (1H, dd, J=5.2,11.7 Hz), 4.39 (1H, dd, J=1.8, 11.7 Hz), 4.45-4.55 (1H, m), 5.05-5.15(1H, m), 6.70-6.80 (2H, m), 7.00-7.15 (2H, m)

TEST EXAMPLE 1 Assay for Inhibitory Effect on Human SGLT2 Activity 1)Construction of the Plasmid Vector Expressing Human SGLT2

Preparation of the cDNA Library for PCR Amplification was performed byreverse transcription of a total RNA deprived from human kidney (Origene) with oligo dT as the primer, using SUPERSCRIPT PreamplificationSystem (Gibco-BRL: LIFE TECHNOLOGIES). The DNA fragment coding for humanSGLT2 was amplified by the PCR reaction, in which the human kidney cDNAlibrary described above was used as the template and the following oligonucleotides 0702F and 0712R, presented as sequence number 1 and 2respectively, were used as the primers. The amplified DNA fragment wasligated into pCR-Blunt (Invitrogen), a vector for cloning, according tostandard method of the kit. The Escherichia coli HB101 was transformedaccording to usual method and then selection of the transformants wasperformed on the LB agar medium containing 50 plasmid DNA was extractedand purified from the one of the transformants, amplifying of the DNAfragment coding for human SGLT2 was performed by the PCR reaction, inwhich the following oligo nucleotides 0714F and 0715R, presented assequence number 3 and 4 respectively, were used as the primers. Theamplified DNA fragment was digested with restriction enzymes, Xho I andHind III, and then purified with Wizard Purification System (Promega).This purified DNA fragment was inserted at into the correspondingrestriction sites of pcDNA3.1 (−) Myc/His-B (Invitrogen), a vector forexpressing of fusion protein. The Escherichia coli HB101 was transformedaccording to usual method and then selection of the transformant wasperformed on the LB agar medium containing 100 plasmid DNA was extractedand purified from this transformant, the base sequence of the DNAfragment inserted at the multi-cloning sites of the vector pcDNA3.1 (−)Myc/His-B was analyzed. This clone had a single base substitution (ATCwhich codes for the isoleucine-433 was substituted by GTC) compared withthe human SGLT2 reported by Wells et al (Am. J. Physiol., Vol. 263, pp.459-465 (1992)). Sequentially, a clone in which valine is substitutedfor isoleucine-433 was obtained. This plasmid vector expressing humanSGLT2 in which the peptide presented as sequence number 5 is fused tothe carboxyl terminal alanine residue was designated KL29.

Sequence Number 1 ATGGAGGAGCACACAGAGGC Sequence Number 2GGCATAGAAGCCCCAGAGGA Sequence Number 3 AACCTCGAGATGGAGGAGCACACAGAGGCSequence Number 4 AACAAGCTTGGCATAGAAGCCCCAGAGGA Sequence Number 5KLGPEQKLISEEDLNSAVDHHHHHH

2) Preparation of the Cells Expressing Transiently Human SGLT2

KL29, the plasmid coding human SGLT2, was transfected into COS-7 cells(RIKEN CELL BANK RCB0539) by electroporation. Electroporation wasperformed with GENE PULSER II (Bio-Rad Laboratories) under thecondition: 0.290 kV, 975 μF, 2×10⁶ cells of COS-7 cell and 20 pg of KL29in 500 μL of OPTI-MEM I medium (Gibco-BRL: LIFE TECHNOLOGIES) in the 0.4cm type cuvette. After the gene transfer, the cells were harvested bycentrifugation and resuspended with OPTI-MEM I medium (1 mL/cuvette). Toeach well in 96-wells plate, 125 μL of this cell suspension was added.After overnight culture at 37° C. under 5% CO₂, 125 μL of DMEM mediumwhich is containing 10% of fetal bovine serum (Sanko Jyunyaku), 100units/mL sodium penicillin G (Gibco-BRL: LIFE TECHNOLOGIES), 100 μg/mLstreptomycin sulfate (Gibco-BRL: LIFE TECHNOLOGIES) was added to eachwell. These cells were cultured until the next day and then they wereused for the measurement of the inhibitory activity against the uptakeof methyl-α-D-glucopyranoside.

3) Measurement of the Inhibitory Activity Against the Uptake ofmethyl-α-D-glucopyranoside

After a test compounds was dissolved in dimethyl sulfoxide and dilutedwith the uptake buffer (a pH 7.4 buffer containing 140 mM sodiumchloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesiumchloride, 5 mM methyl-α-D-glucopyranoside, 10 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acid and 5 mMtris(hydroxymethyl)aminomethane), each diluent was used as test samplefor measurement of the inhibitory activity. After removal of the mediumof the COS-7 cells expressing transiently human SGLT2, to each well 200μL of the pretreatment buffer (a pH 7.4 buffer containing 140 mM cholinechloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesiumchloride, 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acidand 5 mM tris(hydroxymethyl)aminomethane) was added, and the cells wereincubated at 37° C. for 10 minutes. After the pretreatment buffer wasremoved, 200 μL of the same buffer was added again, and the cells wereincubated at 37° C. for 10 minutes. The buffer for measurement wasprepared by adding of 7 μL of methyl-α-D-(U-14C)glucopyranoside(Amersham Pharmacia Biotech) to 525 μL of the prepared test sample. Forthe control, the buffer for measurement without test compound wasprepared. For estimate of the basal uptake in the absence of testcompound and sodium, the buffer for measurement of the basal uptake,which contains 140 mM choline chloride in place of sodium chloride, wasprepared similarly. After the pretreatment buffer was removed, 75 μL ofthe each buffer for measurement was added to each well, the cells wereincubated at 37° C. for 2 hours. After the buffer for measurement wasremoved, 200 μL of the washing buffer (a pH 7.4 buffer containing 140 mMcholine chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mMmagnesium chloride, 10 mM methyl-α-D-glucopyranoside, 10 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acid and 5 mMtris(hydroxymethyl)aminomethane) was added to each well and immediatelyremoved. After two additional washing, the cells were solubilized byaddition of 75 μL of 0.2 mol/L sodium hydroxide to each well. After thecell lysates were transferred to the PicoPlate (Packard) and 150 μL ofMicroScint-40 (Packard) was added to each well, the radioactivity wasmeasured with microplate scintillation counter TopCount (Packard). Thedifference in uptake was obtained as 100% value by subtracting theradioactivity in the basal uptake from that in control and then theconcentrations at which 50% of uptake were inhibited (IC₅₀) werecalculated from the concentration-inhibition curve by least squaremethod. The results are shown in the following Table 3.

TABLE 3 Test compound IC₅₀ value (nM) Reference Example 37 181 ReferenceExample 38 441 Reference Example 39 346 Reference Example 40 702Reference Example 41 185 Reference Example 45 84 Reference Example 46509 Reference Example 47 441 Reference Example 48 679 Reference Example50 415 Reference Example 51 383 Reference Example 54 835 ReferenceExample 57 280 Reference Example 58 190 Reference Example 60 634Reference Example 72 369 WAY-123783 >100000

TEST EXAMPLE 2 Assay for Oral Absorbability

1) Preparation of the Samples for Measurement of the Drug Concentrationafter Intravenous Injection to the Tail Vein

As experimental animal, overnight fasted SD rats (CLEA JAPAN, INC.,male, 5 weeks of age, 140-170 g) were used. Sixty mg of a test compoundwas dissolved by adding of 1.8 mL of ethanol, 7.2 mL of polyethyleneglycol 400 and 9 mL of saline, and then 3.3 mg/mL solution was prepared.The body weights of rats were measured and the solution of the testcompound was intravenously injected to the tail vein of unanesthetizedrats at the dose of 3 mL/kg (10 mg/kg). The intravenous injection to thetail was performed with 26 G injection needle and 1 mL syringe. Thesampling times for collection of blood were 2, 5, 10, 20, 30, 60 and 120minutes after the intravenous injection to the tail. The blood wascentrifuged and the plasma was used as the sample for measurement of thedrug concentration in plasma.

2) Preparation of the Samples for Measurement of the Drug Concentrationafter Oral Administration

As experimental animal, overnight fasted SD rats (CLEA JAPAN, INC.,male, 5 weeks of age, 140-170 g) were used. A test compound wassuspended or dissolved in 0.5% sodium carboxymethylcellulose solution atthe concentration of 1 mg/mL of active form. When homogenous suspensionwas not obtained in this condition, the test compound was dissolved inethanol at the concentration of 100 mg/mL of active form and thensuspension was obtained by adding this solution to 99 times volumes of0.5% sodium carboxymethylcellulose solution. After the body weights ofrats were measured, the liquid containing test compound described abovewas orally administered at the dose of 10 mL/kg (10 mg/kg as activeform). The oral administration was performed with gastric tube for ratand 2.5 mL syringe. The sampling times for collection of blood were 15,30, 60, 120 and 240 minutes after the oral administration. The blood wascentrifuged and the plasma was used as the sample for measurement of thedrug concentration in plasma.

3) Measurement of Drug Concentration Method A

To 0.1 mL of the plasma obtained in 1) and 2) described above, anadequate amount of an adequate internal standard material was addedaccording to usual method and then deproteinization was performed byadding of 1 mL of methanol. After centrifugation, the methanol phase wasevaporated to dryness under a stream of nitrogen. The residue wasdissolved in 300 μL of the mobile phase and 30 μL aliquot of thesolution was injected into HPLC. The drug concentration in plasma wasmeasured by HPLC method under the condition as follows. To 0.1 mL of theblank plasma an adequate internal standard and various concentrations ofcorresponding active form of the compound were adequately addedaccording to usual method, similar operating described above was doneand then the standard curve was prepared.

Column: Develosil ODS-UG-5 (4.6×250 mm)

Mobile phase: acetonitrile/10 mM phosphate buffer (pH 3.0)=22: 78 (v/v)Column temperature: 50° C.Flow rate: 1.0 mL/minuteWavelength for measurement: UV 232 nm

Method B

To 50 μL of the plasma obtained in 1) and 2) described above, anadequate amount of an adequate internal standard material was addedaccording to usual method and 100 μl of distilled water was added, andthen extraction was performed by adding of 1 mL of diethyl ether. Aftercentrifugation, the diethyl ether phase was evaporated to dryness undera stream of nitrogen. The residue was dissolved in 200 μL of the mobilephase and 10 μL aliquot of the solution was injected into LC-MS/MS. Thedrug concentration in plasma was measured by LC-MS/MS method under thecondition as follows. To 50 μL of the blank plasma an adequate internalstandard and various concentrations of corresponding active form ofcompound were adequately added according to usual method, similaroperating described above was done and then the standard curve wasprepared

LC Column: Symmetry C₈ (2.1×20 mm)

Mobile phase: acetonitrile/0.1% acetic acid solution=65: 35 (v/v)Column temperature: 40° C.Flow rate: 0.2 mL/minute

MS/MS

Ionization method: ESI (Turbo Ion Spray), positive ion detection modeIon spray voltage: 5000 VHeater gas temperature: 450° C.Collision energy: 17.5 VMultiplier voltage: 2300 VFlow rate of turbo ion spray gas: 7000 mL/min

Nebulizer gas: 11 BIT Curtain gas: 11 BIT Collision gas: 4 BIT

Each area under the plasma concentration-time curve by intravenousinjection to the tail vein and oral administration of test compound wasestimated with WinNonlin Standard made by Pharsight Corporation from theplasma concentrations at each time obtained from method A and B and thenthe bioavailability (%) was calculated based on the following formula.The results are shown in the following Table 4.

Bioavailability(%)=(Area under the Plasma Concentration−Time Curve byOral Administration/Area under the Plasma Concentration−Time Curve byIntravenous Injection to the Tail Vein)×100

TABLE 4 Test compound Method Bioavailability(%) Example 1 B 27 Example15 B 27 Example 16 B 32 Example 47 A 15 Example 48 A 11 ReferenceExample 37 A 0

TEST EXAMPLE 3 Assay for the Facilitatory Effect on Urinary GlucoseExcretion

As experimental animal, overnight fasted SD rats (Japan SLC. Inc., male,7 weeks of age, 202-221 g) were used. A Test compound was suspended in0.5% sodium carboxymethylcellulose solution at the concentration of 2mg/mL. When homogenous suspension was not obtained in this condition,the test compound was dissolved in ethanol at the concentration of 200mg/mL of active form and then 2 mg/mL suspension was obtained by addingthis solution to 99 times volumes of 0.5% sodium carboxymethylcellulosesolution. A part of this suspension was diluted with 0.5% sodiumcarboxymethylcellulose solution and then 0.6 and 0.2 mg/mL suspensionswere prepared. After the body weights of rats were measured, the testsuspension was orally administered at the dose of 5 mL/kg (1, 3 and 10mg/kg). For control, just only 0.5% sodium carboxymethylcellulosesolution was orally administered at the dose of 5 mL/kg. Immediatelyafter this oral administration, 400 g/L glucose solution was orallyadministered at the dose of 5 mL/kg (2 g/kg). The oral administrationwas performed with gastric tube for rat and 2.5 mL syringe. The headcount in one group was 3. Collection of urine was performed in metaboliccage after the glucose administration was finished. The sampling timefor collection of urine was 24 hours after the glucose administration.After collection of urine was finished, the urine volume was recordedand the urinary glucose concentration was measured. The glucoseconcentration was measured with a kit for laboratory test: GlucoseB-Test WAKO (Wako Pure Chemical Industries, Ltd.). The amount of urinaryglucose excretion in 24 hours per 200 g of body weight was calculatedfrom urine volume, urinary glucose concentration and body weight. Theresults are shown in the following Table 5.

TABLE 5 Amount of Urinary Glucose Excretion Dose (mg/24 hours · 200 gbody Test compound (mg/kg) weight) Example 1 1 1.6 3 28.3 10 127.5Example 15 1 1.7 3 36.8 10 167.3

TEST EXAMPLE 4 Acute Toxicity Test

After 4 week old male ICR mice (Japan SLC. Inc., 20-25 g, 5 animals ineach group) were fasted for 4 hours, the suspension (200 mg/mL) preparedby adding of 0.5% sodium carboxymethylcellulose solution to the testcompound was orally administered at the dose of 10 mL/kg (2000 mg/kg).Observation was performed until 24 hours after the administration. Theresults are shown in the following Table 6.

TABLE 6 Test compound Death number Example 48 0/5

INDUSTRIAL APPLICABILITY

The glucopyranosyloxypyrazole derivatives represented by the abovegeneral formula (I) of the present invention or pharmaceuticallyacceptable salts thereof have an improved oral absorption. In addition,they show an excellent hypoglycemic effect by excreting excess glucoseinto the urine through preventing the reabsorption of glucose at thekidney because they are converted into glucopyranosyloxypyrazolederivatives represented by the above general formula (II) as theiractive forms in vivo and exhibit a potent inhibitory activity in humanSGLT2. Therefore, the present invention can provide agents for theprevention or treatment of a disease associated with hyperglycemia suchas diabetes, diabetic complications, obesity or the like, which are alsosuitable as oral formulations.

[Sequence Listing Free Text]

-   Sequence Number 1: Synthetic DNA primer-   Sequence Number 2: Synthetic DNA primer-   Sequence Number 3: Synthetic DNA primer-   Sequence Number 4: Synthetic DNA primer-   Sequence Number 5: Peptide fused to the carboxyl terminal alanine    residue of human SGLT2

1-37. (canceled)
 38. A method for the prevention of diabetes whichcomprises administering to a patient in need thereof an effective amountof3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazoleor a pharmaceutically acceptable salt thereof.
 39. A method for theprevention as claimed in claim 38, wherein said compound orpharmaceutically acceptable salt thereof is orally administered.